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Jeong T, Lee MS, Jeon J, Park JH, Chung Y, Yang HS. Advanced stem cell therapy using both cell spheroids transplant and paracrine factor release hydrogel patches for myocardial infarction. Colloids Surf B Biointerfaces 2025; 253:114772. [PMID: 40378458 DOI: 10.1016/j.colsurfb.2025.114772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 04/25/2025] [Accepted: 05/06/2025] [Indexed: 05/19/2025]
Abstract
Conventional micro-concave systems have been proposed as effective methods for facile cell spheroid formation, culture. However, these systems face challenges in terms of ease of cell transplantation and a low cell survival rate in ischemic disease. We present a novel open/close type hydrogel micro-concave patch (OC) designed for in situ 3D cell spheroid formation, culture, and a transplantable system utilizing a 3D printed mold. Open-type patches were fabricated with a rigid hydrogel, while closed-type patches were prepared with a combination of swellable soft hydrogel and rigid hydrogel. The open-type concave was intended for cell spheroid formation and subsequent transplantation into the ischemic region. Conversely, the close-type concave allowed released cytokines from cell spheroids, which were located inside the concave, to promote survival of transplanted cell spheroid. We hypothesized that transplant of open-type cell spheroids, combined with the release of paracrine factors from close-type cell spheroids, could enhance therapeutic outcomes in ischemic regions. The OC was prepared using different concentration ratios of swellable polyacrylamide (PAAM) hydrogel through 3D printed micropillar mold. Additionally, PAAM was characterized to enhance the compactness of close-type 3D cell spheroids. Transplantation of OC improved the therapeutic effect in a rat cardiac infarction model compared to open-type patches.
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Affiliation(s)
- Taekgwang Jeong
- Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea
| | - Min Suk Lee
- Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea; Richard and Loan Hill Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Jin Jeon
- Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea; Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology, Hwarang-ro 14-gil 5, Seongbuk-gu, Seoul 02792, Republic of Korea
| | - Jin Hee Park
- Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea
| | - Youngdoo Chung
- Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea
| | - Hee Seok Yang
- Department of Nanobiomedical Science & BK21 FOUR NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan 31116, Republic of Korea; Department of Biomedical Science & Engineering, Dankook University, Cheonan 31116, Republic of Korea; Center for Bio-Medical Engineering Core-Facility, Dankook University, Cheonan 31116, Republic of Korea.
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2
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Tang XL, Alloosh M, Ou Q, Luo L, Agrawal DK, Kalra DK, Sturek M, Bolli R. A new model of heart failure with preserved ejection fraction induced by metabolic syndrome in Ossabaw miniature swine. Basic Res Cardiol 2025:10.1007/s00395-025-01112-1. [PMID: 40312575 DOI: 10.1007/s00395-025-01112-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Revised: 04/21/2025] [Accepted: 04/22/2025] [Indexed: 05/03/2025]
Abstract
A major obstacle to progress in heart failure with preserved ejection fraction (HFpEF) is the paucity of clinically relevant animal models. We developed a large, translationally relevant model in Ossabaw minipigs, which are genetically predisposed to the metabolic syndrome (MetS). Pigs were fed a "Western diet" high in calories, fructose, fat, cholesterol, and salt and received 1-2 deoxy-corticosterone acetate (DOCA) depots (n = 10). After 6 months, they exhibited liver function abnormalities and marked increases in body weight, arterial blood pressure, serum cholesterol and triglycerides, and plasma glucose and insulin levels (glucose tolerance test), indicating the development of a full MetS. Echocardiography demonstrated no change in LV ejection fraction but progressive concentric LV hypertrophy and left atrial dilatation. Doppler echocardiography showed increased E/e' ratio and increased peak early (E) and peak late atrial (A) transmitral inflow velocities, with no change in E/A ratio. Right heart catheterization demonstrated increased central venous pressure, pulmonary arterial systolic pressure, and pulmonary capillary wedge pressure. Clinically, pigs exhibited impaired exercise capacity, assessed by treadmill tests, associated with chronotropic incompetence. Pathologic examination showed significant myocardial fibrosis, myocyte hypertrophy, and liver fibrosis. In contrast, lean pigs fed a standard diet (n = 3) did not show any changes at 6 months. The Ossabaw porcine model described herein is unique in that it recapitulates the entire constellation of major multiorgan comorbidities and hemodynamic, clinical, and metabolic features of MetS-driven human HFpEF: obesity, arterial hypertension, hyperlipidemia, glucose intolerance, insulin resistance, liver fibrosis and dysfunction, pulmonary hypertension, increased LV filling pressures, concentric LV hypertrophy, LV diastolic dysfunction with preserved systolic function, and impaired exercise capacity. Because of its high clinical relevance, this model is well-suited for exploring the pathophysiology of MetS-driven HFpEF and the efficacy of new therapies.
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Affiliation(s)
- Xian-Liang Tang
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | - Mouhamad Alloosh
- CorVus Biomedical, LLC and CorVus Foundation, Inc, Indianapolis, USA
| | - Qinghui Ou
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | - Li Luo
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | | | - Dinesh K Kalra
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | - Michael Sturek
- CorVus Biomedical, LLC and CorVus Foundation, Inc, Indianapolis, USA
| | - Roberto Bolli
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA.
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3
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Tang XL, Wysoczynski M, Gumpert AM, Solanki M, Li Y, Wu WJ, Zheng S, Ruble H, Li H, Stowers H, Zheng S, Ou Q, Tanveer N, Slezak J, Kalra DK, Bolli R. Intravenous infusions of mesenchymal stromal cells have cumulative beneficial effects in a porcine model of chronic ischaemic cardiomyopathy. Cardiovasc Res 2024; 120:1939-1952. [PMID: 39163570 PMCID: PMC11630033 DOI: 10.1093/cvr/cvae173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 07/08/2024] [Accepted: 07/23/2024] [Indexed: 08/22/2024] Open
Abstract
AIMS The development of cell therapy as a widely available clinical option for ischaemic cardiomyopathy is hindered by the invasive nature of current cell delivery methods. Furthermore, the rapid disappearance of cells after transplantation provides a cogent rationale for using repeated cell doses, which, however, has not been done thus far in clinical trials because it is not feasible with invasive approaches. The goal of this translational study was to test the therapeutic utility of the intravenous route for cell delivery. METHODS AND RESULTS Pigs with chronic ischaemic cardiomyopathy induced by myocardial infarction received one or three intravenous doses of allogeneic bone marrow mesenchymal stromal cells (MSCs) or placebo 35 days apart. Rigour guidelines, including blinding and randomization, were strictly followed. A comprehensive assessment of left ventricular (LV) function was conducted with three independent methods (echocardiography, magnetic resonance imaging, and haemodynamic studies). The results demonstrate that three doses of MSCs improved both load-dependent and independent indices of LV function and reduced myocardial hypertrophy and fibrosis; in contrast, one dose failed to produce most of these benefits. CONCLUSIONS To our knowledge, this is the first study to show that intravenous infusion of a cell product improves LV function and structure in a large animal model of chronic ischaemic cardiomyopathy and that repeated infusions are necessary to produce robust effects. This study, conducted in a clinically relevant model, supports a new therapeutic strategy based on repeated intravenous infusions of allogeneic MSCs and provides a foundation for a first-in-human trial testing this strategy in patients with chronic ischaemic cardiomyopathy.
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Affiliation(s)
- Xian-Liang Tang
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Marcin Wysoczynski
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Anna M Gumpert
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Mitesh Solanki
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Yan Li
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Wen-Jian Wu
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Shirong Zheng
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Halina Ruble
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Hong Li
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Heather Stowers
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Shengnan Zheng
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Qinghui Ou
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Nida Tanveer
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Jan Slezak
- Centre of Experimental Medicine, Institute for Heart Research, Bratislava, Slovakia
| | - Dinesh K Kalra
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Roberto Bolli
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
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Yahyazadeh R, Baradaran Rahimi V, Askari VR. Stem cell and exosome therapies for regenerating damaged myocardium in heart failure. Life Sci 2024; 351:122858. [PMID: 38909681 DOI: 10.1016/j.lfs.2024.122858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/13/2024] [Accepted: 06/18/2024] [Indexed: 06/25/2024]
Abstract
Finding novel treatments for cardiovascular diseases (CVDs) is a hot topic in medicine; cell-based therapies have reported promising news for controlling dangerous complications of heart disease such as myocardial infarction (MI) and heart failure (HF). Various progenitor/stem cells were tested in various in-vivo, in-vitro, and clinical studies for regeneration or repairing the injured tissue in the myocardial to accelerate the healing. Fetal, adult, embryonic, and induced pluripotent stem cells (iPSC) have revealed the proper potency for cardiac tissue repair. As an essential communicator among cells, exosomes with specific contacts (proteins, lncRNAs, and miRNAs) greatly promote cardiac rehabilitation. Interestingly, stem cell-derived exosomes have more efficiency than stem cell transplantation. Therefore, stem cells induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), cardiac stem cells (CDC), and skeletal myoblasts) and their-derived exosomes will probably be considered an alternative therapy for CVDs remedy. In addition, stem cell-derived exosomes have been used in the diagnosis/prognosis of heart diseases. In this review, we explained the advances of stem cells/exosome-based treatment, their beneficial effects, and underlying mechanisms, which will present new insights in the clinical field in the future.
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Affiliation(s)
- Roghayeh Yahyazadeh
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vafa Baradaran Rahimi
- Department of Cardiovascular Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Vahid Reza Askari
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran.
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Tasdemiroglu Y, Council-Troche M, Chen M, Ledford B, Norris RA, Poelzing S, Gourdie RG, He JQ. Degradation of the α-Carboxyl Terminus 11 Peptide: In Vivo and Ex Vivo Impacts of Time, Temperature, Inhibitors, and Gender in Rat. ACS Pharmacol Transl Sci 2024; 7:1624-1636. [PMID: 38751644 PMCID: PMC11091968 DOI: 10.1021/acsptsci.4c00120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 04/03/2024] [Accepted: 04/08/2024] [Indexed: 05/18/2024]
Abstract
In previous research, a synthetic α-carboxyl terminus 1 (αCT1) peptide derived from connexin 43 (Cx43) and its variant (αCT11) showed beneficial effects in an ex vivo ischemia-reperfusion (I/R) heart injury model in mouse. In an in vivo mouse model of cryo-induced ventricular injury, αCT1 released from adhesive cardiac patches reduced Cx43 remodeling and arrhythmias, as well as maintained cardiac conduction. Whether intravenous injection of αCT1 or αCT11 produces similar outcomes has not been investigated. Given the possibility of peptide degradation in plasma, this study utilized in vivo I/R cardiac injury and ex vivo blood plasma models to examine factors that may limit the therapeutic potential of peptide therapeutics in vivo. Following tail vein administration of αCT11 (100 μM) in blood, no effect on I/R infarct size was observed in adult rat hearts on day 1 (D1) and day 28 (D28) after injury (p > 0.05). There was also no difference in the echocardiographic ejection fraction (EF%) between the control and the αCT11 groups (p > 0.05). Surprisingly, αCT11 in blood plasma collected from these rats was undetectable within ∼10 min after tail vein injection. To investigate factors that may modulate αCT11 degradation in blood, αCT11 was directly added to blood plasma isolated from normal rats without I/R and peptide levels were measured under different experimental conditions. Consistent with in vivo observations, significant αCT11 degradation occurred in plasma within 10 min at 22 and 37 °C and was nearly undetectable by 30 min. These responses were reduced by the addition of protease/phosphatase (PTase/PPTase) inhibitors to the isolated plasma. Interestingly, no significant differences in αCT11 degradation in plasma were noted between male and female rats. We conclude that fast degradation of αCT11 is likely the reason that no beneficial effects were observed in the in vivo I/R model and inhibition or shielding from PTase/PPTase activity may be a strategy that will assist with the viability of peptide therapeutics.
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Affiliation(s)
- Yagmur Tasdemiroglu
- Department
of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, 225 Duck Pond Drive, Blacksburg, Virginia 24061, United States
| | - McAlister Council-Troche
- Department
of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, 225 Duck Pond Drive, Blacksburg, Virginia 24061, United States
| | - Miao Chen
- Department
of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, 225 Duck Pond Drive, Blacksburg, Virginia 24061, United States
| | - Benjamin Ledford
- Department
of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, 225 Duck Pond Drive, Blacksburg, Virginia 24061, United States
| | - Russell A. Norris
- Department
of Medicine, Medical University of South
Carolina, Charleston, South Carolina 29425, United States
| | - Steven Poelzing
- Center
for Vascular and Heart Research, Fralin Biomedical Research Institute, Virginia Tech, 2 Riverside Circle, Roanoke, Virginia 24016, United States
| | - Robert G. Gourdie
- Center
for Vascular and Heart Research, Fralin Biomedical Research Institute, Virginia Tech, 2 Riverside Circle, Roanoke, Virginia 24016, United States
| | - Jia-Qiang He
- Department
of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, 225 Duck Pond Drive, Blacksburg, Virginia 24061, United States
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6
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Olejarz W, Sadowski K, Radoszkiewicz K. Extracellular Vesicles in Atherosclerosis: State of the Art. Int J Mol Sci 2023; 25:388. [PMID: 38203558 PMCID: PMC10779125 DOI: 10.3390/ijms25010388] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 12/17/2023] [Accepted: 12/25/2023] [Indexed: 01/12/2024] Open
Abstract
Atherosclerosis is a chronic inflammatory disease driven by lipid accumulation in the arteries, leading to narrowing and thrombosis that causes mortality. Emerging evidence has confirmed that atherosclerosis affects younger people and is involved in the majority of deaths worldwide. EVs are associated with critical steps in atherosclerosis, cholesterol metabolism, immune response, endothelial dysfunction, vascular inflammation, and remodeling. Endothelial cell-derived EVs can interact with platelets and monocytes, thereby influencing endothelial dysfunction, atherosclerotic plaque destabilization, and the formation of thrombus. EVs are potential diagnostic and prognostic biomarkers in atherosclerosis (AS) and cardiovascular disease (CVD). Importantly, EVs derived from stem/progenitor cells are essential mediators of cardiogenesis and cardioprotection and may be used in regenerative medicine and tissue engineering.
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Affiliation(s)
- Wioletta Olejarz
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 02-091 Warsaw, Poland;
- Centre for Preclinical Research, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Karol Sadowski
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, 02-091 Warsaw, Poland;
- Centre for Preclinical Research, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Klaudia Radoszkiewicz
- Translational Platform for Regenerative Medicine, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland;
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7
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Chepeleva EV. Cell Therapy in the Treatment of Coronary Heart Disease. Int J Mol Sci 2023; 24:16844. [PMID: 38069167 PMCID: PMC10706847 DOI: 10.3390/ijms242316844] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Heart failure is a leading cause of death in patients who have suffered a myocardial infarction. Despite the timely use of modern reperfusion therapies such as thrombolysis, surgical revascularization and balloon angioplasty, they are sometimes unable to prevent the development of significant areas of myocardial damage and subsequent heart failure. Research efforts have focused on developing strategies to improve the functional status of myocardial injury areas. Consequently, the restoration of cardiac function using cell therapy is an exciting prospect. This review describes the characteristics of various cell types relevant to cellular cardiomyoplasty and presents findings from experimental and clinical studies investigating cell therapy for coronary heart disease. Cell delivery methods, optimal dosage and potential treatment mechanisms are discussed.
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Affiliation(s)
- Elena V. Chepeleva
- Federal State Budgetary Institution National Medical Research Center Named after Academician E.N. Meshalkin of the Ministry of Health of the Russian Federation, 15, Rechkunovskaya Str., 630055 Novosibirsk, Russia;
- Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics Siberian Branch of Russian Academy of Sciences, 2, Timakova Str., 630060 Novosibirsk, Russia
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8
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Tang XL, Nasr M, Zheng S, Zoubul T, Stephan JK, Uchida S, Singhal R, Khan A, Gumpert A, Bolli R, Wysoczynski M. Bone Marrow and Wharton's Jelly Mesenchymal Stromal Cells are Ineffective for Myocardial Repair in an Immunodeficient Rat Model of Chronic Ischemic Cardiomyopathy. Stem Cell Rev Rep 2023; 19:2429-2446. [PMID: 37500831 PMCID: PMC10579184 DOI: 10.1007/s12015-023-10590-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/09/2023] [Indexed: 07/29/2023]
Abstract
BACKGROUND Although cell therapy provides benefits for outcomes of heart failure, the most optimal cell type to be used clinically remains unknown. Most of the cell products used for therapy in humans require in vitro expansion to obtain a suitable number of cells for treatment; however, the clinical background of the donor and limited starting material may result in the impaired proliferative and reparative capacity of the cells expanded in vitro. Wharton's jelly mesenchymal cells (WJ MSCs) provide a multitude of advantages over adult tissue-derived cell products for therapy. These include large starting tissue material, superior proliferative capacity, and disease-free donors. Thus, WJ MSC if effective would be the most optimal cell source for clinical use. OBJECTIVES This study evaluated the therapeutic efficacy of Wharton's jelly (WJ) and bone marrow (BM) mesenchymal stromal cells (MSCs) in chronic ischemic cardiomyopathy in rats. METHODS Human WJ MSCs and BM MSCs were expanded in vitro, characterized, and evaluated for therapeutic efficacy in a immunodeficient rat model of ischemic cardiomyopathy. Cardiac function was evaluated with hemodynamics and echocardiography. The extent of cardiac fibrosis, hypertrophy, and inflammation was assessed with histological analysis. RESULTS In vitro analysis revealed that WJ MSCs and BM MSCs are morphologically and immunophenotypically indistinguishable. Nevertheless, the functional analysis showed that WJ MSCs have a superior proliferative capacity, less senescent phenotype, and distinct transcriptomic profile compared to BM MSC. WJ MSCs and BM MSC injected in rat hearts chronically after MI produced a small, but not significant improvement in heart structure and function. Histological analysis showed no difference in the scar size, collagen content, cardiomyocyte cross-sectional area, and immune cell count. CONCLUSIONS Human WJ and BM MSC have a small but not significant effect on cardiac structure and function when injected intramyocardially in immunodeficient rats chronically after MI.
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Affiliation(s)
- Xian-Liang Tang
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Marjan Nasr
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston St. - Rm 204B, Louisville, KY, 40202, USA
| | - Shirong Zheng
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston St. - Rm 204B, Louisville, KY, 40202, USA
| | - Taylor Zoubul
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston St. - Rm 204B, Louisville, KY, 40202, USA
| | - Jonah K Stephan
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston St. - Rm 204B, Louisville, KY, 40202, USA
| | - Shizuka Uchida
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - Richa Singhal
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston St. - Rm 204B, Louisville, KY, 40202, USA
| | - Aisha Khan
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Anna Gumpert
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Roberto Bolli
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Marcin Wysoczynski
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston St. - Rm 204B, Louisville, KY, 40202, USA.
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9
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Tonkin D, Yee-Goh A, Katare R. Healing the Ischaemic Heart: A Critical Review of Stem Cell Therapies. Rev Cardiovasc Med 2023; 24:122. [PMID: 39076280 PMCID: PMC11273058 DOI: 10.31083/j.rcm2404122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/16/2023] [Accepted: 03/20/2023] [Indexed: 07/31/2024] Open
Abstract
Ischaemic heart disease (IHD) remains the leading cause of mortality worldwide. Current pharmaceutical treatments focus on delaying, rather than preventing disease progression. The only curative treatment available is orthotopic heart transplantation, which is greatly limited by a lack of available donors and the possibility for immune rejection. As a result, novel therapies are consistently being sought to improve the quality and duration of life of those suffering from IHD. Stem cell therapies have garnered attention globally owing to their potential to replace lost cardiac cells, regenerate the ischaemic myocardium and to release protective paracrine factors. Despite recent advances in regenerative cardiology, one of the biggest challenges in the clinical translation of cell-based therapies is determining the most efficacious cell type for repair. Multiple cell types have been investigated in clinical trials; with inconsistent methodologies and isolation protocols making it difficult to draw strong conclusions. This review provides an overview of IHD focusing on pathogenesis and complications, followed by a summary of different stem cells which have been trialled for use in the treatment of IHD, and ends by exploring the known mechanisms by which stem cells mediate their beneficial effects on ischaemic myocardium.
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Affiliation(s)
- Devin Tonkin
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, 9010 Dunedin, New Zealand
| | - Anthony Yee-Goh
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, 9010 Dunedin, New Zealand
| | - Rajesh Katare
- Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, 9010 Dunedin, New Zealand
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10
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Administration of stem cells against cardiovascular diseases with a focus on molecular mechanisms: Current knowledge and prospects. Tissue Cell 2023; 81:102030. [PMID: 36709696 DOI: 10.1016/j.tice.2023.102030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 01/15/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023]
Abstract
Cardiovascular diseases (CVDs) are a serious global concern for public and human health. Despite the emergence of significant therapeutic advances, it is still the leading cause of death and disability worldwide. As a result, extensive efforts are underway to develop practical therapeutic approaches. Stem cell-based therapies could be considered a promising strategy for the treatment of CVDs. The efficacy of stem cell-based therapeutic approaches is demonstrated through recent laboratory and clinical studies due to their inherent regenerative properties, proliferative nature, and their capacity to differentiate into different cells such as cardiomyocytes. These properties could improve cardiovascular functioning leading to heart regeneration. The two most common types of stem cells with the potential to cure heart diseases are induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs). Several studies have demonstrated the use, efficacy, and safety of MSC and iPSCs-based therapies for the treatment of CVDs. In this study, we explain the application of stem cells, especially iPSCs and MSCs, in the treatment of CVDs with a focus on cellular and molecular mechanisms and then discuss the advantages, disadvantages, and perspectives of using this technology in the treatment of these diseases.
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11
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Chao CM, Wang LY, Huang CC, Chang WT, Tang LY, Lin MT, Chang CP. Myocardial structure and functional alterations in a preclinical model of exertional heat stroke. Life Sci 2023; 323:121640. [PMID: 37004732 DOI: 10.1016/j.lfs.2023.121640] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 03/17/2023] [Accepted: 03/24/2023] [Indexed: 04/03/2023]
Abstract
AIM Relatively little information is available about the effect of an acute exertional heat stroke (EHS) on myocardium structure and function. Herein, we used a survival male rat model of EHS to answer the question. MAIN METHODS Adult male Wistar rats underwent forced treadmill running at a 36 °C room temperature and 50 % relative humidity until EHS onset, characterized by hyperthermia and collapse. All rats that were followed for 14 days survived. Injury severity scores of both gastrocnemius and myocardium were determined histologically. Following an EHS event, pathological echocardiography, skeletal muscle and myocardial damage scores and indicators, myocardial fibrosis, hypertrophy, and autophagy were elucidated. KEY FINDINGS Rats with EHS onset displayed skeletal muscle damage, elevated serum levels of skeletal muscle indicators (e.g., creatinine kinase, myoglobin, and potassium) and myocardial injury indicators (e.g., cardiac troponin I, creatinine kinase, and lactate dehydrogenase) returning to homeostasis within 3 days post-EHS. However, EHS-induced myocardial damage, pathological echocardiography, myocardial fibrosis, hypertrophy, and deposited misfolded proteins lasted up to 14 days post-EHS at least. SIGNIFICANCE First, we provide evidence to confirm that despite the apparent return to homeostasis, underlying processes may still be ongoing after EHS onset. Second, we provide several key findings emphasizing the pathophysiology and risk factors of EHS, highlighting gaps in knowledge with the aim of stimulating future studies.
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12
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Babanejad N, Mfoafo K, Thumma A, Omidi Y, Omidian H. Advances in cryostructures and their applications in biomedical and pharmaceutical products. Polym Bull (Berl) 2023. [DOI: 10.1007/s00289-023-04683-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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13
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Li QL, Tang J, Zhao L, Ruze A, Shan XF, Gao XM. The role of CD74 in cardiovascular disease. Front Cardiovasc Med 2023; 9:1049143. [PMID: 36712241 PMCID: PMC9877307 DOI: 10.3389/fcvm.2022.1049143] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 12/21/2022] [Indexed: 01/15/2023] Open
Abstract
Leukocyte differentiation antigen 74 (CD74), also known as invariant chain, is a molecular chaperone of major histocompatibility complex class II (MHC II) molecules involved in antigen presentation. CD74 has recently been shown to be a receptor for the macrophage migration inhibitory factor family proteins (MIF/MIF2). Many studies have revealed that CD74 plays an important role in cardiovascular disease. In this review, we summarize the structure and main functions of CD74 and then focus on the recent research progress on the role of CD74 in cardiovascular diseases. In addition, we also discuss potential treatment strategies that target CD74. Our systematic review of the role of CD74 in cardiovascular disease will fill some knowledge gaps in the field.
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Affiliation(s)
- Qiu-Lin Li
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asian, Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China,Xinjiang Key Laboratory of Medical Animal Model Research, Ürümqi, China
| | - Jing Tang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asian, Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China,Xinjiang Key Laboratory of Medical Animal Model Research, Ürümqi, China,Department of Clinical Laboratory, The First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | - Ling Zhao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asian, Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China,Xinjiang Key Laboratory of Medical Animal Model Research, Ürümqi, China
| | - Amanguli Ruze
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asian, Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China,Xinjiang Key Laboratory of Medical Animal Model Research, Ürümqi, China
| | - Xue-Feng Shan
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asian, Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China,Xinjiang Key Laboratory of Medical Animal Model Research, Ürümqi, China
| | - Xiao-Ming Gao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asian, Department of Cardiology, The First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China,Xinjiang Key Laboratory of Medical Animal Model Research, Ürümqi, China,Clinical Medical Research Institute of Xinjiang Medical University, Ürümqi, China,*Correspondence: Xiao-Ming Gao,
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14
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Kaur N, Sharma RK, Singh Kushwah A, Singh N, Thakur S. A Comprehensive Review of Dilated Cardiomyopathy in Pre-clinical Animal Models in Addition to Herbal Treatment Options and Multi-modality Imaging Strategies. Cardiovasc Hematol Disord Drug Targets 2023; 22:207-225. [PMID: 36734898 DOI: 10.2174/1871529x23666230123122808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/05/2022] [Accepted: 11/17/2022] [Indexed: 02/01/2023]
Abstract
Dilated cardiomyopathy (DCM) is distinguished by ventricular chamber expansion, systolic dysfunction, and normal left ventricular (LV) wall thickness, and is mainly caused due to genetic or environmental factors; however, its aetiology is undetermined in the majority of patients. The focus of this work is on pathogenesis, small animal models, as well as the herbal medicinal approach, and the most recent advances in imaging modalities for patients with dilated cardiomyopathy. Several small animal models have been proposed over the last few years to mimic various pathomechanisms that contribute to dilated cardiomyopathy. Surgical procedures, gene mutations, and drug therapies are all characteristic features of these models. The pros and cons, including heart failure stimulation of extensively established small animal models for dilated cardiomyopathy, are illustrated, as these models tend to procure key insights and contribute to the development of innovative treatment techniques for patients. Traditional medicinal plants used as treatment in these models are also discussed, along with contemporary developments in herbal therapies. In the last few decades, accurate diagnosis, proper recognition of the underlying disease, specific risk stratification, and forecasting of clinical outcome, have indeed improved the health of DCM patients. Cardiac magnetic resonance (CMR) is the bullion criterion for assessing ventricular volume and ejection fraction in a reliable and consistent direction. Other technologies, like strain analysis and 3D echocardiography, have enhanced this technique's predictive and therapeutic potential. Nuclear imaging potentially helps doctors pinpoint the causative factors of left ventricular dysfunction, as with cardiac sarcoidosis and amyloidosis.
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Affiliation(s)
- Navneet Kaur
- Department of Pharmacology, Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial College of Pharmacy, Bela, Ropar, Punjab, India
| | - Rahul Kumar Sharma
- Department of Pharmacology, Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial College of Pharmacy, Bela, Ropar, Punjab, India
| | - Ajay Singh Kushwah
- Department of Pharmacology, Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial College of Pharmacy, Bela, Ropar, Punjab, India
| | - Nisha Singh
- Department of Pharmacology, Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial College of Pharmacy, Bela, Ropar, Punjab, India
| | - Shilpa Thakur
- Department of Pharmacology, Amar Shaheed Baba Ajit Singh Jujhar Singh Memorial College of Pharmacy, Bela, Ropar, Punjab, India
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15
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Shen L, Fan G, Yang G, Yang Z, Gui C. Paracrine effects of mir-210-3p on angiogenesis in hypoxia-treated c-kit-positive cardiac cells. Ann Med 2023; 55:2237690. [PMID: 37480581 PMCID: PMC10364570 DOI: 10.1080/07853890.2023.2237690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 07/01/2023] [Accepted: 07/12/2023] [Indexed: 07/24/2023] Open
Abstract
Objective: Treatment with c-kit-positive cardiac cells (CPCs) has been shown to improve the prognosis of ischemic heart disease. MicroRNAs (miRNAs) confer protection by enhancing the cardiac repair process, but their specific functional mechanisms remain unclear. This study aimed to screen for differentially expressed miRNAs in CPCs under hypoxia and explore their effects on the function of CPCs.Methods: We harvested CPCs from C57 adult mice and later performed a high-throughput miRNA sequencing for differential expression profiling analysis. Subsequently, we intervened with the differentially expressed gene miR-210-3p in CPCs and detected changes in the secretion of angiogenesis-related factors through a protein-chip analysis. Finally, we applied CPC supernatants of different groups as conditioned medium to treat mouse cardiac microvascular endothelial cells (CMECs) and further investigated the functional effects of miR-210-3p on c-kit+CPCs under ischemia and hypoxia conditions.Results: The miR-210-3p was highly increased in hypoxia-treated CPCs. Protein-chip detection revealed that CPCs expressed cytokines such as FGF basic, angiogenin, and vascular endothelial growth factor (VEGF) and that hypoxia enhanced their release. Silencing miR-210-3p resulted in a reduction in the release of these angiogenesis-related factors. In addition, the conditioned medium of hypoxia-treated CPCs promoted the proliferation, migration, and tube-forming capabilities of CMECs. In contrast, the conditioned media of CPCs with silenced miR-210-3p after hypoxia decreased the proliferation, migration, and tube-forming ability of CMEC.Conclusions: The CPCs exert proangiogenic effects via paracrine pathways mediated by miR-210-3p. Upregulation of miR-210-3p in hypoxia-treated CPCs may enhance their paracrine function by regulating the secretion of angiogenic factors, thereby promoting angiogenesis in ischemic heart disease.
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Affiliation(s)
- Louyi Shen
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory Base of Precision Medicine in Cardiocerebrovascular Diseases Control and Prevention, Nanning, China
- Guangxi Clinical Research Center for Cardiocerebrovascular Diseases, Nanning, China
| | - Guan Fan
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory Base of Precision Medicine in Cardiocerebrovascular Diseases Control and Prevention, Nanning, China
- Guangxi Clinical Research Center for Cardiocerebrovascular Diseases, Nanning, China
| | - Guoliang Yang
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory Base of Precision Medicine in Cardiocerebrovascular Diseases Control and Prevention, Nanning, China
- Guangxi Clinical Research Center for Cardiocerebrovascular Diseases, Nanning, China
| | - Zhijie Yang
- Department of Cardiology, Liuzhou People's Hospital, Liuzhou, China
| | - Chun Gui
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory Base of Precision Medicine in Cardiocerebrovascular Diseases Control and Prevention, Nanning, China
- Guangxi Clinical Research Center for Cardiocerebrovascular Diseases, Nanning, China
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16
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Nummi A, Pätilä T, Mulari S, Lampinen M, Nieminen T, Mäyränpää MI, Vento A, Harjula A, Kankuri E. Epicardial transplantation of autologous atrial appendage micrografts: evaluation of safety and feasibility in pigs after coronary artery occlusion. SCAND CARDIOVASC J 2022; 56:352-360. [PMID: 36002941 DOI: 10.1080/14017431.2022.2111462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/04/2022] [Accepted: 08/05/2022] [Indexed: 06/15/2023]
Abstract
Objectives. Several approaches devised for clinical utilization of cell-based therapies for heart failure often suffer from complex and lengthy preparation stages. Epicardial delivery of autologous atrial appendage micrografts (AAMs) with a clinically used extracellular matrix (ECM) patch provides a straightforward therapy alternative. We evaluated the operative feasibility and the effect of micrografts on the patch-induced epicardial foreign body inflammatory response in a porcine model of myocardial infarction. Design. Right atrial appendages were harvested and mechanically processed into AAMs. The left anterior descending coronary artery was ligated to generate acute infarction. Patches of ECM matrix with or without AAMs were transplanted epicardially onto the infarcted area. Four pigs received the ECM and four received the AAMs patch. Cardiac function was studied by echocardiography both preoperatively and at 3-week follow-up. The primary outcome measures were safety and feasibility of the therapy administration, and the secondary outcome was the inflammatory response to ECM. Results. Neither AAMs nor ECM patch-related complications were detected during the follow-up time. AAMs patch preparation was feasible according to time and safety. Inflammation was greatly reduced in AAMs when compared with ECM patches as measured by the amount of infiltrated inflammatory cells and area of inflammation. Immunohistochemistry demonstrated an increased CD3+ cell density in the AAMs patch infiltrate. Conclusions. Epicardial AAMs transplantation demonstrated safety and clinical feasibility. The use of micrografts significantly inhibited ECM-induced foreign body inflammatory reactivity. Transplantation of AAMs shows good clinical applicability as adjuvant therapy to cardiac surgery and can suppress acute inflammatory reactivity.
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Affiliation(s)
- Annu Nummi
- Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Tommi Pätilä
- Pediatric Cardiac Surgery, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Severi Mulari
- Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Milla Lampinen
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Tuomo Nieminen
- Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Päijät-Häme Joint Authority for Health and Wellbeing, Lahti, Finland
| | - Mikko I Mäyränpää
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Antti Vento
- Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Ari Harjula
- Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Esko Kankuri
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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17
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Assessment of Myocardial Diastolic Dysfunction as a Result of Myocardial Infarction and Extracellular Matrix Regulation Disorders in the Context of Mesenchymal Stem Cell Therapy. J Clin Med 2022; 11:jcm11185430. [PMID: 36143077 PMCID: PMC9502668 DOI: 10.3390/jcm11185430] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/05/2022] [Accepted: 09/13/2022] [Indexed: 11/16/2022] Open
Abstract
The decline in cardiac contractility due to damage or loss of cardiomyocytes is intensified by changes in the extracellular matrix leading to heart remodeling. An excessive matrix response in the ischemic cardiomyopathy may contribute to the elevated fibrotic compartment and diastolic dysfunction. Fibroproliferation is a defense response aimed at quickly closing the damaged area and maintaining tissue integrity. Balance in this process is of paramount importance, as the reduced post-infarction response causes scar thinning and more pronounced left ventricular remodeling, while excessive fibrosis leads to impairment of heart function. Under normal conditions, migration of progenitor cells to the lesion site occurs. These cells have the potential to differentiate into myocytes in vitro, but the changed micro-environment in the heart after infarction does not allow such differentiation. Stem cell transplantation affects the extracellular matrix remodeling and thus may facilitate the improvement of left ventricular function. Studies show that mesenchymal stem cell therapy after infarct reduces fibrosis. However, the authors did not specify whether they meant the reduction of scarring as a result of regeneration or changes in the matrix. Research is also necessary to rule out long-term negative effects of post-acute infarct stem cell therapy.
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18
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Femminò S, Bonelli F, Brizzi MF. Extracellular vesicles in cardiac repair and regeneration: Beyond stem-cell-based approaches. Front Cell Dev Biol 2022; 10:996887. [PMID: 36120584 PMCID: PMC9479097 DOI: 10.3389/fcell.2022.996887] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 08/16/2022] [Indexed: 11/13/2022] Open
Abstract
The adult human heart poorly regenerate after injury due to the low self-renewal capability retained by adult cardiomyocytes. In the last two decades, several clinical studies have reported the ability of stem cells to induce cardiac regeneration. However, low cell integration and survival into the tissue has limited stem-cell-based clinical approaches. More recently, the release of paracrine mediators including extracellular vesicles (EV) has been recognized as the most relevant mechanism driving benefits upon cell-based therapy. In particular, EV have emerged as key mediators of cardiac repair after damage, in terms of reduction of apoptosis, resolution of inflammation and new blood vessel formation. Herein, mechanisms involved in cardiac damage and regeneration, and current applications of EV and their small non-coding RNAs (miRNAs) in regenerative medicine are discussed.
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19
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Enhancement strategy for effective vascular regeneration following myocardial infarction through a dual stem cell approach. EXPERIMENTAL & MOLECULAR MEDICINE 2022; 54:1165-1178. [PMID: 35974098 PMCID: PMC9440102 DOI: 10.1038/s12276-022-00827-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 03/08/2022] [Accepted: 03/21/2022] [Indexed: 11/08/2022]
Abstract
Since an impaired coronary blood supply following myocardial infarction (MI) negatively affects heart function, therapeutic neovascularization is considered one of the major therapeutic strategies for cell-based cardiac repair. Here, to more effectively achieve therapeutic neovascularization in ischemic hearts, we developed a dual stem cell approach for effective vascular regeneration by utilizing two distinct types of stem cells, CD31+-endothelial cells derived from human induced pluripotent stem cells (hiPSC-ECs) and engineered human mesenchymal stem cells that continuously secrete stromal derived factor-1α (SDF-eMSCs), to simultaneously promote natal vasculogenesis and angiogenesis, two core mechanisms of neovascularization. To induce more comprehensive vascular regeneration, we intramyocardially injected hiPSC-ECs to produce de novo vessels, possibly via vasculogenesis, and a 3D cardiac patch encapsulating SDF-eMSCs (SDF-eMSC-PA) to enhance angiogenesis through prolonged secretion of paracrine factors, including SDF-1α, was implanted into the epicardium of ischemic hearts. We verified that hiPSC-ECs directly contribute to de novo vessel formation in ischemic hearts, resulting in enhanced cardiac function. In addition, the concomitant implantation of SDF1α-eMSC-PAs substantially improved the survival, retention, and vasculogenic potential of hiPSC-ECs, ultimately achieving more comprehensive neovascularization in the MI hearts. Of note, the newly formed vessels through the dual stem cell approach were significantly larger and more functional than those formed by hiPSC-ECs alone. In conclusion, these results provide compelling evidence that our strategy for effective vascular regeneration can be an effective means to treat ischemic heart disease. A treatment involving two different types of stem cells leads to repairing failed hearts by making new functional blood vessels. Researchers at the City University of Hong Kong and the Catholic University of Korea induced heart attacks in rats before injecting the hearts with endothelial cells derived from human induced pluripotent stem cells, specialized to form blood vessels. These cells successfully induced the formation of new blood vessels in the damaged hearts. The researchers combined this treatment with a cardiac patch containing engineered human adult stem cells, which improved the survival and performance of the endothelial cells. And this dual stem cell treatment resulted in enhanced cardiac function and a higher number of larger and stronger new blood vessels than those produced by the single-cell treatment suggesting an effective way to repair failed hearts.
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20
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Li D, Tian K, Guo J, Wang Q, Qin Z, Lu Y, Xu Y, Scott N, Charles CJ, Liu G, Zhang J, Cui X, Tang J. Growth factors: avenues for the treatment of myocardial infarction and potential delivery strategies. Regen Med 2022; 17:561-579. [PMID: 35638395 DOI: 10.2217/rme-2022-0007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Acute myocardial infarction (AMI) is one of the leading causes of death worldwide. Despite recent advances in clinical management, reoccurence of heart failure after AMI remains high, in part because of the limited capacity of cardiac tissue to repair after AMI-induced cell death. Growth factor-based therapy has emerged as an alternative AMI treatment strategy. Understanding the underlying mechanisms of growth factor cardioprotective and regenerative actions is important. This review focuses on the function of different growth factors at each stage of the cardiac repair process. Recent evidence for growth factor therapy in preclinical and clinical trials is included. Finally, different delivery strategies are reviewed with a view to providing workable strategies for clinical translation.
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Affiliation(s)
- Demin Li
- Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, 450052, China.,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, 450052, China
| | - Kang Tian
- Department of Bone and Joint, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116000, China
| | - Jiacheng Guo
- Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, 450052, China.,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, 450052, China
| | - Qiguang Wang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, 610065, China
| | - Zhen Qin
- Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, 450052, China.,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, 450052, China
| | - Yongzheng Lu
- Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, 450052, China.,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, 450052, China
| | - Yanyan Xu
- Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, 450052, China.,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, 450052, China
| | - Nicola Scott
- Department of Medicine, Christchurch Heart Institute, University of Otago, Christchurch, 8011, New Zealand
| | - Chris J Charles
- Department of Orthopedic Surgery and Musculoskeletal Medicine, Christchurch Regenerative Medicine and Tissue Engineering Group, University of Otago, Christchurch, 8011, New Zealand
| | - Guozhen Liu
- School of Life and Health Sciences, Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, 518172, China
| | - Jinying Zhang
- Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, 450052, China.,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, 450052, China
| | - Xiaolin Cui
- Department of Bone and Joint, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116000, China.,Department of Orthopedic Surgery and Musculoskeletal Medicine, Christchurch Regenerative Medicine and Tissue Engineering Group, University of Otago, Christchurch, 8011, New Zealand
| | - Junnan Tang
- Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.,Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, 450052, China.,Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, 450052, China
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21
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Li X, Wang X, He P, Bennett E, Haggard E, Ma J, Cai C. Mitochondrial Membrane Potential Identifies a Subpopulation of Mesenchymal Progenitor Cells to Promote Angiogenesis and Myocardial Repair. Cells 2022; 11:1713. [PMID: 35626749 PMCID: PMC9139404 DOI: 10.3390/cells11101713] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 12/10/2022] Open
Abstract
Identifying effective donor cells is one of obstacles that limits cell therapy for heart disease. In this study, we sorted a subpopulation of human mesenchymal progenitor cells (hMPCs) from the right atrial appendage using the low mitochondrial membrane potential. Compared to the non-sorted cells, hMPCs hold the capacity for stemness and enrich mesenchymal stem cell markers. The hMPCs display better ability for survival, faster proliferation, less production of reactive oxygen species (ROS), and greater release of cytoprotective cytokines. The hMPCs exhibit decreased expression of senescence genes and increased expression of anti-apoptotic and antioxidant genes. Intramyocardial injection of hMPCs into the infarcted heart resulted in increased left ventricular ejection fraction and reduced cardiac remodeling and infarct size in the group of animals receiving hMPCs. Both in vitro and in vivo studies indicated hMPCs have the potential to differentiate into endothelial cells and smooth muscle cells. Immunohistochemistry staining showed that cell therapy with hMPCs enhances cardiac vascular regeneration and cardiac proliferation, and decreases cardiac cell apoptosis, which is associated with the increased secretion of cytoprotective and pro-angiogenic cytokines. Overall, we discovered a subpopulation of human mesenchymal progenitor cells via their low mitochondrial membrane potential, which might provide an alternative donor cell source for cellular therapy for ischemic heart disease.
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Affiliation(s)
- Xiuchun Li
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (X.L.); (X.W.); (E.H.); (J.M.)
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY 12208, USA;
| | - Xiaoliang Wang
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (X.L.); (X.W.); (E.H.); (J.M.)
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY 12208, USA;
| | - Pan He
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY 12208, USA;
| | - Edward Bennett
- Division of Cardiothoracic Surgery, Albany Medical Center, Albany, NY 12208, USA;
| | - Erin Haggard
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (X.L.); (X.W.); (E.H.); (J.M.)
| | - Jianjie Ma
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (X.L.); (X.W.); (E.H.); (J.M.)
| | - Chuanxi Cai
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; (X.L.); (X.W.); (E.H.); (J.M.)
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY 12208, USA;
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22
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Tang XL, Wysoczynski M, Gumpert AM, Li Y, Wu WJ, Li H, Stowers H, Bolli R. Effect of intravenous cell therapy in rats with old myocardial infarction. Mol Cell Biochem 2022; 477:431-444. [PMID: 34783963 PMCID: PMC8896398 DOI: 10.1007/s11010-021-04283-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 10/21/2021] [Indexed: 10/19/2022]
Abstract
Mounting evidence shows that cell therapy provides therapeutic benefits in experimental and clinical settings of chronic heart failure. However, direct cardiac delivery of cells via transendocardial injection is logistically complex, expensive, entails risks, and is not amenable to multiple dosing. Intravenous administration would be a more convenient and clinically applicable route for cell therapy. Thus, we determined whether intravenous infusion of three widely used cell types improves left ventricular (LV) function and structure and compared their efficacy. Rats with a 30-day-old myocardial infarction (MI) received intravenous infusion of vehicle (PBS) or 1 of 3 types of cells: bone marrow mesenchymal stromal cells (MSCs), cardiac mesenchymal cells (CMCs), and c-kit-positive cardiac cells (CPCs), at a dose of 12 × 106 cells. Rats were followed for 35 days after treatment to determine LV functional status by serial echocardiography and hemodynamic studies. Blood samples were collected for Hemavet analysis to determine inflammatory cell profile. LV ejection fraction (EF) dropped ≥ 20 points in all hearts at 30 days after MI and deteriorated further at 35-day follow-up in the vehicle-treated group. In contrast, deterioration of EF was halted in rats that received MSCs and attenuated in those that received CMCs or CPCs. None of the 3 types of cells significantly altered scar size, myocardial content of collagen or CD45-positive cells, or Hemavet profile. This study demonstrates that a single intravenous administration of 3 types of cells in rats with chronic ischemic cardiomyopathy is effective in attenuating the progressive deterioration in LV function. The extent of LV functional improvement was greatest with CPCs, intermediate with CMCs, and least with MSCs.
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Affiliation(s)
- Xian-Liang Tang
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | - Marcin Wysoczynski
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | - Anna M Gumpert
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | - Yan Li
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | - Wen-Jian Wu
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | - Hong Li
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | - Heather Stowers
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA
| | - Roberto Bolli
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY, 40202, USA.
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Effects of Heme Oxygenase-1 on c-Kit-Positive Cardiac Cells. Int J Mol Sci 2021; 22:ijms222413448. [PMID: 34948245 PMCID: PMC8704354 DOI: 10.3390/ijms222413448] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/09/2021] [Accepted: 12/12/2021] [Indexed: 01/02/2023] Open
Abstract
Heme oxygenase-1 (HO-1) is one of the most powerful cytoprotective proteins known. The goal of this study was to explore the effects of HO-1 in c-kit-positive cardiac cells (CPCs). LinNEG/c-kitPOS CPCs were isolated and expanded from wild-type (WT), HO-1 transgenic (TG), or HO-1 knockout (KO) mouse hearts. Compared with WT CPCs, cell proliferation was significantly increased in HO-1TG CPCs and decreased in HO-1KO CPCs. HO-1TG CPCs also exhibited a marked increase in new DNA synthesis during the S-phase of cell division, not only under normoxia (21% O2) but after severe hypoxia (1% O2 for 16 h). These properties of HO-1TG CPCs were associated with nuclear translocation (and thus activation) of Nrf2, a key transcription factor that regulates antioxidant genes, and increased protein expression of Ec-SOD, the only extracellular antioxidant enzyme. These data demonstrate that HO-1 upregulates Ec-SOD in CPCs and suggest that this occurs via activation of Nrf2, which thus is potentially involved in the crosstalk between two antioxidants, HO-1 in cytoplasm and Ec-SOD in extracellular matrix. Overexpression of HO-1 in CPCs may improve the survival and reparative ability of CPCs after transplantation and thus may have potential clinical application to increase efficacy of cell therapy.
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Martínez-Falguera D, Iborra-Egea O, Gálvez-Montón C. iPSC Therapy for Myocardial Infarction in Large Animal Models: Land of Hope and Dreams. Biomedicines 2021; 9:1836. [PMID: 34944652 PMCID: PMC8698445 DOI: 10.3390/biomedicines9121836] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/30/2021] [Accepted: 12/01/2021] [Indexed: 02/07/2023] Open
Abstract
Myocardial infarction is the main driver of heart failure due to ischemia and subsequent cell death, and cell-based strategies have emerged as promising therapeutic methods to replace dead tissue in cardiovascular diseases. Research in this field has been dramatically advanced by the development of laboratory-induced pluripotent stem cells (iPSCs) that harbor the capability to become any cell type. Like other experimental strategies, stem cell therapy must meet multiple requirements before reaching the clinical trial phase, and in vivo models are indispensable for ensuring the safety of such novel therapies. Specifically, translational studies in large animal models are necessary to fully evaluate the therapeutic potential of this approach; to empirically determine the optimal combination of cell types, supplementary factors, and delivery methods to maximize efficacy; and to stringently assess safety. In the present review, we summarize the main strategies employed to generate iPSCs and differentiate them into cardiomyocytes in large animal species; the most critical differences between using small versus large animal models for cardiovascular studies; and the strategies that have been pursued regarding implanted cells' stage of differentiation, origin, and technical application.
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Affiliation(s)
- Daina Martínez-Falguera
- Faculty of Medicine, University of Barcelona (UB), 08036 Barcelona, Spain;
- ICREC Research Program, Germans Trias i Pujol Health Research Institute, Can Ruti Campus, 08916 Badalona, Spain;
- Heart Institute (iCor), Germans Trias i Pujol University Hospital, 08916 Badalona, Spain
| | - Oriol Iborra-Egea
- ICREC Research Program, Germans Trias i Pujol Health Research Institute, Can Ruti Campus, 08916 Badalona, Spain;
- Heart Institute (iCor), Germans Trias i Pujol University Hospital, 08916 Badalona, Spain
| | - Carolina Gálvez-Montón
- ICREC Research Program, Germans Trias i Pujol Health Research Institute, Can Ruti Campus, 08916 Badalona, Spain;
- Heart Institute (iCor), Germans Trias i Pujol University Hospital, 08916 Badalona, Spain
- CIBERCV, Instituto de Salud Carlos III, 28029 Madrid, Spain
- Institut d’Investigació Biomèdica de Bellvitge-IDIBELL, L’Hospitalet de Llobregat, 08908 Barcelona, Spain
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25
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Yousefi-Ahmadipour A, Asadi F, Pirsadeghi A, Nazeri N, Vahidi R, Abazari MF, Afgar A, Mirzaei-Parsa MJ. Current Status of Stem Cell Therapy and Nanofibrous Scaffolds in Cardiovascular Tissue Engineering. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2021. [DOI: 10.1007/s40883-021-00230-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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26
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Wiśniewska J, Sadowska A, Wójtowicz A, Słyszewska M, Szóstek-Mioduchowska A. Perspective on Stem Cell Therapy in Organ Fibrosis: Animal Models and Human Studies. Life (Basel) 2021; 11:life11101068. [PMID: 34685439 PMCID: PMC8538998 DOI: 10.3390/life11101068] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 12/17/2022] Open
Abstract
Tissue fibrosis is characterized by excessive deposition of extracellular matrix (ECM) components that result from the disruption of regulatory processes responsible for ECM synthesis, deposition, and remodeling. Fibrosis develops in response to a trigger or injury and can occur in nearly all organs of the body. Thus, fibrosis leads to severe pathological conditions that disrupt organ architecture and cause loss of function. It has been estimated that severe fibrotic disorders are responsible for up to one-third of deaths worldwide. Although intensive research on the development of new strategies for fibrosis treatment has been carried out, therapeutic approaches remain limited. Since stem cells, especially mesenchymal stem cells (MSCs), show remarkable self-renewal, differentiation, and immunomodulatory capacity, they have been intensively tested in preclinical studies and clinical trials as a potential tool to slow down the progression of fibrosis and improve the quality of life of patients with fibrotic disorders. In this review, we summarize in vitro studies, preclinical studies performed on animal models of human fibrotic diseases, and recent clinical trials on the efficacy of allogeneic and autologous stem cell applications in severe types of fibrosis that develop in lungs, liver, heart, kidney, uterus, and skin. Although the results of the studies seem to be encouraging, there are many aspects of cell-based therapy, including the cell source, dose, administration route and frequency, timing of delivery, and long-term safety, that remain open areas for future investigation. We also discuss the contemporary status, challenges, and future perspectives of stem cell transplantation for therapeutic options in fibrotic diseases as well as we present recent patents for stem cell-based therapies in organ fibrosis.
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27
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Audam TN, Howard CM, Garrett LF, Zheng YW, Bradley JA, Brittian KR, Frank MW, Fulghum KL, Pólos M, Herczeg S, Merkely B, Radovits T, Uchida S, Hill BG, Dassanayaka S, Jackowski S, Jones SP. Cardiac PANK1 deletion exacerbates ventricular dysfunction during pressure overload. Am J Physiol Heart Circ Physiol 2021; 321:H784-H797. [PMID: 34533403 PMCID: PMC8794231 DOI: 10.1152/ajpheart.00411.2021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/03/2021] [Accepted: 09/03/2021] [Indexed: 12/13/2022]
Abstract
Coenzyme A (CoA) is an essential cofactor required for intermediary metabolism. Perturbations in homeostasis of CoA have been implicated in various pathologies; however, whether CoA homeostasis is changed and the extent to which CoA levels contribute to ventricular function and remodeling during pressure overload has not been explored. In this study, we sought to assess changes in CoA biosynthetic pathway during pressure overload and determine the impact of limiting CoA on cardiac function. We limited cardiac CoA levels by deleting the rate-limiting enzyme in CoA biosynthesis, pantothenate kinase 1 (Pank1). We found that constitutive, cardiomyocyte-specific Pank1 deletion (cmPank1-/-) significantly reduced PANK1 mRNA, PANK1 protein, and CoA levels compared with Pank1-sufficient littermates (cmPank1+/+) but exerted no obvious deleterious impact on the mice at baseline. We then subjected both groups of mice to pressure overload-induced heart failure. Interestingly, there was more ventricular dilation in cmPank1-/- during the pressure overload. To explore potential mechanisms contributing to this phenotype, we performed transcriptomic profiling, which suggested a role for Pank1 in regulating fibrotic and metabolic processes during the pressure overload. Indeed, Pank1 deletion exacerbated cardiac fibrosis following pressure overload. Because we were interested in the possibility of early metabolic impacts in response to pressure overload, we performed untargeted metabolomics, which indicated significant changes to metabolites involved in fatty acid and ketone metabolism, among other pathways. Collectively, our study underscores the role of elevated CoA levels in supporting fatty acid and ketone body oxidation, which may be more important than CoA-driven, enzyme-independent acetylation in the failing heart.NEW & NOTEWORTHY Changes in CoA homeostasis have been implicated in a variety of metabolic diseases; however, the extent to which changes in CoA homeostasis impacts remodeling has not been explored. We show that limiting cardiac CoA levels via PANK deletion exacerbated ventricular remodeling during pressure overload. Our results suggest that metabolic alterations, rather than structural alterations, associated with Pank1 deletion may underlie the exacerbated cardiac phenotype during pressure overload.
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Affiliation(s)
- Timothy N Audam
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Caitlin M Howard
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Lauren F Garrett
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Yi Wei Zheng
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - James A Bradley
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Kenneth R Brittian
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Matthew W Frank
- Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Kyle L Fulghum
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Miklós Pólos
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Szilvia Herczeg
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Béla Merkely
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Tamás Radovits
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Shizuka Uchida
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Bradford G Hill
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Sujith Dassanayaka
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Suzanne Jackowski
- Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Steven P Jones
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
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28
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Prat-Vidal C, Crisóstomo V, Moscoso I, Báez-Díaz C, Blanco-Blázquez V, Gómez-Mauricio G, Albericio G, Aguilar S, Fernández-Santos ME, Fernández-Avilés F, Sánchez-Margallo FM, Bayes-Genis A, Bernad A. Intracoronary Delivery of Porcine Cardiac Progenitor Cells Overexpressing IGF-1 and HGF in a Pig Model of Sub-Acute Myocardial Infarction. Cells 2021; 10:cells10102571. [PMID: 34685551 PMCID: PMC8534140 DOI: 10.3390/cells10102571] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 09/17/2021] [Accepted: 09/24/2021] [Indexed: 12/26/2022] Open
Abstract
Human cardiac progenitor cells (hCPC) are considered a good candidate in cell therapy for ischemic heart disease, demonstrating capacity to improve functional recovery after myocardial infarction (MI), both in small and large preclinical animal models. However, improvements are required in terms of cell engraftment and efficacy. Based on previously published reports, insulin-growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) have demonstrated substantial cardioprotective, repair and regeneration activities, so they are good candidates to be evaluated in large animal model of MI. We have validated porcine cardiac progenitor cells (pCPC) and lentiviral vectors to overexpress IGF-1 (co-expressing eGFP) and HGF (co-expressing mCherry). pCPC were transduced and IGF1-eGFPpos and HGF-mCherrypos populations were purified by cell sorting and further expanded. Overexpression of IGF-1 has a limited impact on pCPC expression profile, whereas results indicated that pCPC-HGF-mCherry cultures could be counter selecting high expresser cells. In addition, pCPC-IGF1-eGFP showed a higher cardiogenic response, evaluated in co-cultures with decellularized extracellular matrix, compared with native pCPC or pCPC-HGF-mCherry. In vivo intracoronary co-administration of pCPC-IGF1-eGFP and pCPC-HFG-mCherry (1:1; 40 × 106/animal), one week after the induction of an MI model in swine, revealed no significant improvement in cardiac function.
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Affiliation(s)
- Cristina Prat-Vidal
- ICREC Research Program, Germans Trias i Pujol Health Science Research Institute, Can Ruti Campus, Heart Institute (iCor), Germans Trias i Pujol University Hospital, 08916 Badalona, Spain; (C.P.-V.); (A.B.-G.)
- CIBERCV, Instituto de Salud Carlos III, 28029 Madrid, Spain; (V.C.); (I.M.); (C.B.-D.); (V.B.-B.); (M.-E.F.-S.); (F.F.-A.); (F.M.S.-M.)
- Institut d’Investigació Biomèdica de Bellvitge-IDIBELL, 08908 L’Hospitalet de Llobregat, Spain
| | - Verónica Crisóstomo
- CIBERCV, Instituto de Salud Carlos III, 28029 Madrid, Spain; (V.C.); (I.M.); (C.B.-D.); (V.B.-B.); (M.-E.F.-S.); (F.F.-A.); (F.M.S.-M.)
- Jesús Usón Minimally Invasive Surgery Center, 10071 Cáceres, Spain;
| | - Isabel Moscoso
- CIBERCV, Instituto de Salud Carlos III, 28029 Madrid, Spain; (V.C.); (I.M.); (C.B.-D.); (V.B.-B.); (M.-E.F.-S.); (F.F.-A.); (F.M.S.-M.)
- Cardiology Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Universidade de Santiago de Compostela and Health Research Institute, University Clinical Hospital of Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Claudia Báez-Díaz
- CIBERCV, Instituto de Salud Carlos III, 28029 Madrid, Spain; (V.C.); (I.M.); (C.B.-D.); (V.B.-B.); (M.-E.F.-S.); (F.F.-A.); (F.M.S.-M.)
- Jesús Usón Minimally Invasive Surgery Center, 10071 Cáceres, Spain;
| | - Virginia Blanco-Blázquez
- CIBERCV, Instituto de Salud Carlos III, 28029 Madrid, Spain; (V.C.); (I.M.); (C.B.-D.); (V.B.-B.); (M.-E.F.-S.); (F.F.-A.); (F.M.S.-M.)
- Jesús Usón Minimally Invasive Surgery Center, 10071 Cáceres, Spain;
| | | | - Guillermo Albericio
- Immunology and Oncology Department, National Center for Biotechnology, 28049 Madrid, Spain; (G.A.); (S.A.)
| | - Susana Aguilar
- Immunology and Oncology Department, National Center for Biotechnology, 28049 Madrid, Spain; (G.A.); (S.A.)
| | - María-Eugenia Fernández-Santos
- CIBERCV, Instituto de Salud Carlos III, 28029 Madrid, Spain; (V.C.); (I.M.); (C.B.-D.); (V.B.-B.); (M.-E.F.-S.); (F.F.-A.); (F.M.S.-M.)
- Servicio de Cardiología, Hospital General Universitario Gregorio Marañón, Laboratorio Investigación Traslacional en Cardiología (LITC), Unidad de Producción Celular-GMP (UPC-GMP), Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), TERCEL, 28007 Madrid, Spain
| | - Francisco Fernández-Avilés
- CIBERCV, Instituto de Salud Carlos III, 28029 Madrid, Spain; (V.C.); (I.M.); (C.B.-D.); (V.B.-B.); (M.-E.F.-S.); (F.F.-A.); (F.M.S.-M.)
- Servicio de Cardiología, Hospital General Universitario Gregorio Marañón, Laboratorio Investigación Traslacional en Cardiología (LITC), Unidad de Producción Celular-GMP (UPC-GMP), Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), TERCEL, 28007 Madrid, Spain
- Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain
| | - Francisco M. Sánchez-Margallo
- CIBERCV, Instituto de Salud Carlos III, 28029 Madrid, Spain; (V.C.); (I.M.); (C.B.-D.); (V.B.-B.); (M.-E.F.-S.); (F.F.-A.); (F.M.S.-M.)
- Jesús Usón Minimally Invasive Surgery Center, 10071 Cáceres, Spain;
| | - Antoni Bayes-Genis
- ICREC Research Program, Germans Trias i Pujol Health Science Research Institute, Can Ruti Campus, Heart Institute (iCor), Germans Trias i Pujol University Hospital, 08916 Badalona, Spain; (C.P.-V.); (A.B.-G.)
- CIBERCV, Instituto de Salud Carlos III, 28029 Madrid, Spain; (V.C.); (I.M.); (C.B.-D.); (V.B.-B.); (M.-E.F.-S.); (F.F.-A.); (F.M.S.-M.)
- Cardiology Service, Germans Trias i Pujol University Hospital, 08916 Badalona, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Antonio Bernad
- Immunology and Oncology Department, National Center for Biotechnology, 28049 Madrid, Spain; (G.A.); (S.A.)
- Correspondence: ; Tel.: +34-915-855-424
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Human cardiac stem cells rejuvenated by modulating autophagy with MHY-1685 enhance the therapeutic potential for cardiac repair. Exp Mol Med 2021; 53:1423-1436. [PMID: 34584195 PMCID: PMC8492872 DOI: 10.1038/s12276-021-00676-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 05/27/2021] [Accepted: 07/06/2021] [Indexed: 02/08/2023] Open
Abstract
Stem cell-based therapies with clinical applications require millions of cells. Therefore, repeated subculture is essential for cellular expansion, which is often complicated by replicative senescence. Cellular senescence contributes to reduced stem cell regenerative potential as it inhibits stem cell proliferation and differentiation as well as the activation of the senescence-associated secretory phenotype (SASP). In this study, we employed MHY-1685, a novel mammalian target of rapamycin (mTOR) inhibitor, and examined its long-term priming effect on the activities of senile human cardiac stem cells (hCSCs) and the functional benefits of primed hCSCs after transplantation. In vitro experiments showed that the MHY-1685‒primed hCSCs exhibited higher viability in response to oxidative stress and an enhanced proliferation potential compared to that of the unprimed senile hCSCs. Interestingly, priming MHY-1685 enhanced the expression of stemness-related markers in senile hCSCs and provided the differentiation potential of hCSCs into vascular lineages. In vivo experiment with echocardiography showed that transplantation of MHY-1685‒primed hCSCs improved cardiac function than that of the unprimed senile hCSCs at 4 weeks post-MI. In addition, hearts transplanted with MHY-1685-primed hCSCs exhibited significantly lower cardiac fibrosis and higher capillary density than that of the unprimed senile hCSCs. In confocal fluorescence imaging, MHY-1685‒primed hCSCs survived for longer durations than that of the unprimed senile hCSCs and had a higher potential to differentiate into endothelial cells (ECs) within the infarcted hearts. These findings suggest that MHY-1685 can rejuvenate senile hCSCs by modulating autophagy and that as a senescence inhibitor, MHY-1685 can provide opportunities to improve hCSC-based myocardial regeneration.
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Nummi A, Mulari S, Stewart JA, Kivistö S, Teittinen K, Nieminen T, Lampinen M, Pätilä T, Sintonen H, Juvonen T, Kupari M, Suojaranta R, Kankuri E, Harjula A, Vento A, the AADC consortium. Epicardial Transplantation of Autologous Cardiac Micrografts During Coronary Artery Bypass Surgery. Front Cardiovasc Med 2021; 8:726889. [PMID: 34595223 PMCID: PMC8476794 DOI: 10.3389/fcvm.2021.726889] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 08/09/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Cardio-regenerative cell therapies offer additional biologic support to coronary artery bypass surgery (CABG) and are aimed at functionally repairing the myocardium that suffers from or is damaged by ischemia. This non-randomized open-label study assessed the safety and feasibility of epicardial transplantation of atrial appendage micrografts (AAMs) in patients undergoing CABG surgery. Methods: Twelve consecutive patients destined for CABG surgery were included in the study. Six patients received AAMs during their operation and six patients were CABG-operated without AAMs transplantation. Data from 30 elective CABG patients was collected for a center- and time-matched control group. The AAMs were processed during the operation from a biopsy collected from the right atrial appendage. They were delivered epicardially onto the infarct scar site identified in preoperative late gadolinium enhancement cardiac magnetic resonance imaging (CMRI). The primary outcome measures at the 6-month follow-up were (i) patient safety in terms of hemodynamic and cardiac function over time and (ii) feasibility of therapy administration in a clinical setting. Secondary outcome measures were left ventricular wall thickness, change in myocardial scar tissue volume, changes in left ventricular ejection fraction, plasma concentrations of N-terminal pro-B-type natriuretic peptide levels, NYHA class, number of days in hospital and changes in the quality of life. Results: Epicardial transplantation of AAMs was safe and feasible to be performed during CABG surgery. CMRI demonstrated an increase in viable cardiac tissue at the infarct site in patients receiving AAMs treatment. Conclusions and Relevance: Transplantation of AAMs shows good clinical applicability as performed during cardiac surgery, shows initial therapeutic effect on the myocardium and has the potential to serve as a delivery platform for cardiac gene therapies. Trial Registration:ClinicalTrials.gov, identifier: NCT02672163.
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Affiliation(s)
- Annu Nummi
- Heart and Lung Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Severi Mulari
- Heart and Lung Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Juhani A. Stewart
- Heart and Lung Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Sari Kivistö
- Department of Radiology, Helsinki University Hospital (HUS) Medical Imaging Center and Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Kari Teittinen
- Heart and Lung Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Tuomo Nieminen
- Department of Internal Medicine, Päijät-Häme Central Hospital, Lahti, Finland
| | - Milla Lampinen
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Tommi Pätilä
- Pediatric Cardiac Surgery, Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Harri Sintonen
- Department of Public Health, University of Helsinki, Helsinki, Finland
| | - Tatu Juvonen
- Heart and Lung Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Markku Kupari
- Heart and Lung Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Raili Suojaranta
- Department of Anesthesiology and Intensive Care, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Esko Kankuri
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Ari Harjula
- Heart and Lung Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Antti Vento
- Heart and Lung Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
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Arjmand B, Abedi M, Arabi M, Alavi-Moghadam S, Rezaei-Tavirani M, Hadavandkhani M, Tayanloo-Beik A, Kordi R, Roudsari PP, Larijani B. Regenerative Medicine for the Treatment of Ischemic Heart Disease; Status and Future Perspectives. Front Cell Dev Biol 2021; 9:704903. [PMID: 34568321 PMCID: PMC8461329 DOI: 10.3389/fcell.2021.704903] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 07/19/2021] [Indexed: 12/20/2022] Open
Abstract
Cardiovascular disease is now the leading cause of adult death in the world. According to new estimates from the World Health Organization, myocardial infarction (MI) is responsible for four out of every five deaths due to cardiovascular disease. Conventional treatments of MI are taking aspirin and nitroglycerin as intermediate treatments and injecting antithrombotic agents within the first 3 h after MI. Coronary artery bypass grafting and percutaneous coronary intervention are the most common long term treatments. Since none of these interventions will fully regenerate the infarcted myocardium, there is value in pursuing more innovative therapeutic approaches. Regenerative medicine is an innovative interdisciplinary method for rebuilding, replacing, or repairing the missed part of different organs in the body, as similar as possible to the primary structure. In recent years, regenerative medicine has been widely utilized as a treatment for ischemic heart disease (one of the most fatal factors around the world) to repair the lost part of the heart by using stem cells. Here, the development of mesenchymal stem cells causes a breakthrough in the treatment of different cardiovascular diseases. They are easily obtainable from different sources, and expanded and enriched easily, with no need for immunosuppressing agents before transplantation, and fewer possibilities of genetic abnormality accompany them through multiple passages. The production of new cardiomyocytes can result from the transplantation of different types of stem cells. Accordingly, due to its remarkable benefits, stem cell therapy has received attention in recent years as it provides a drug-free and surgical treatment for patients and encourages a more safe and feasible cardiac repair. Although different clinical trials have reported on the promising benefits of stem cell therapy, there is still uncertainty about its mechanism of action. It is important to conduct different preclinical and clinical studies to explore the exact mechanism of action of the cells. After reviewing the pathophysiology of MI, this study addresses the role of tissue regeneration using various materials, including different types of stem cells. It proves some appropriate data about the importance of ethical problems, which leads to future perspectives on this scientific method.
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Affiliation(s)
- Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mina Abedi
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Arabi
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Alavi-Moghadam
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mahdieh Hadavandkhani
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Akram Tayanloo-Beik
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramin Kordi
- Sports Medicine Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Peyvand Parhizkar Roudsari
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Bittle GJ, Morales D, Pietris N, Parchment N, Parsell D, Peck K, Deatrick KB, Rodriguez-Borlado L, Smith RR, Marbán L, Kaushal S. Exosomes isolated from human cardiosphere–derived cells attenuate pressure overload–induced right ventricular dysfunction. J Thorac Cardiovasc Surg 2021; 162:975-986.e6. [DOI: 10.1016/j.jtcvs.2020.06.154] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 06/10/2020] [Accepted: 06/27/2020] [Indexed: 01/27/2023]
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Electrophysiological engineering of heart-derived cells with calcium-dependent potassium channels improves cell therapy efficacy for cardioprotection. Nat Commun 2021; 12:4963. [PMID: 34400625 PMCID: PMC8368210 DOI: 10.1038/s41467-021-25180-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 07/21/2021] [Indexed: 12/30/2022] Open
Abstract
We have shown that calcium-activated potassium (KCa)-channels regulate fundamental progenitor-cell functions, including proliferation, but their contribution to cell-therapy effectiveness is unknown. Here, we test the participation of KCa-channels in human heart explant-derived cell (EDC) physiology and therapeutic potential. TRAM34-sensitive KCa3.1-channels, encoded by the KCNN4 gene, are exclusively expressed in therapeutically bioactive EDC subfractions and maintain a strongly polarized resting potential; whereas therapeutically inert EDCs lack KCa3.1 channels and exhibit depolarized resting potentials. Somatic gene transfer of KCNN4 results in membrane hyperpolarization and increases intracellular [Ca2+], which boosts cell-proliferation and the production of pro-healing cytokines/nanoparticles. Intramyocardial injection of EDCs after KCNN4-gene overexpression markedly increases the salutary effects of EDCs on cardiac function, viable myocardium and peri-infarct neovascularization in a well-established murine model of ischemic cardiomyopathy. Thus, electrophysiological engineering provides a potentially valuable strategy to improve the therapeutic value of progenitor cells for cardioprotection and possibly other indications. Strategies to improve the function of damaged hearts with progenitor cells have stalled. Here, the authors show that gene transfer of a calcium-dependent potassium channel enhances the functional properties and ability of explant-derived cells to improve heart function after a heart attack.
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Chen YT, Chuang FC, Yang CC, Chiang JY, Sung PH, Chu YC, Huang CR, Huang KH, Yip HK. Combined melatonin-adipose derived mesenchymal stem cells therapy effectively protected the testis from testicular torsion-induced ischemia-reperfusion injury. Stem Cell Res Ther 2021; 12:370. [PMID: 34187560 PMCID: PMC8243739 DOI: 10.1186/s13287-021-02439-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/09/2021] [Indexed: 12/02/2022] Open
Abstract
Background This study tested the hypothesis that combined melatonin (Mel) and adipose-derived mesenchymal stem cells (ADMSCs) treatment was superior to either one alone on protecting the testis against acute testicular torsion-induced ischemia-reperfusion (TTIR) injury. Methods and results Male adult SD rats (n = 30) were equally categorized into group 1 (sham-operated control), group 2 [TTIR/by torsion of right/left testis (i.e., ischemia) with rotated 720° counterclockwise for 2 h, then detorsion (i.e., reperfusion) to the original position for 72 h], group 3 (TTIR + Mel/intraperitoneal administration/50 mg/kg at 30 min after ischemia, followed by 20 mg at 3 h and days 1/2/3 after TTIR), group 4 (TTIR + ADMSCs/1.2 × 106 cells/by tail-vein administration at 30 min after ischemia, followed by days 1/2 TTIR), and group 5 (TTIR + Mel + ADMSCs/tail-vein administration). The result showed that the protein expressions of oxidative-stress (NOX-1/NOX-2/oxidized-protein), apoptotic/mitochondrial-damaged (mitochondrial-Bax/cleaved-caspase3/cleaved-PARP/cytosolic-cytochrome C), and fibrotic (TGF-ß/Smad3) biomarkers as well as testicular damage scores were lowest in group 1, highest in group 2, and significantly higher in groups 3/4 than in group 5, but they showed no difference between groups 3/4, whereas the protein expressions of androgen receptor (AR) and vimentin showed an opposite pattern of oxidative stress (all p < 0.0001). The cellular levels of inflammation (MMP-9/MPO/CD68) exhibited an identical pattern, whereas the numbers of Sertoli cells, α-tubulin, AR and vimentin as well as thickness of seminiferous tubule exhibited an opposite pattern of oxidative stress among the groups (all p < 0.0001). Conclusion Mel-ADMSCs effectively protected the testis against TTIR injury.
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Affiliation(s)
- Yen-Ta Chen
- Division of Urology, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Fei-Chi Chuang
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Chih-Chao Yang
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - John Y Chiang
- Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung, Taiwan.,Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Pei-Hsun Sung
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.,Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Yi-Ching Chu
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chi-Ruei Huang
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.,Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kuan-Hui Huang
- Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
| | - Hon-Kan Yip
- Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. .,Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan. .,Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. .,Department of Nursing, Asia University, Taichung, Taiwan. .,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. .,Division of Cardiology, Department of Internal Medicine, Xiamen Chang Gung Hospital, Xiamen, Fujian, China.
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Garbayo E, Ruiz-Villalba A, Hernandez SC, Saludas L, Abizanda G, Pelacho B, Roncal C, Sanchez B, Palacios I, Prósper F, Blanco-Prieto MJ. Delivery of cardiovascular progenitors with biomimetic microcarriers reduces adverse ventricular remodeling in a rat model of chronic myocardial infarction. Acta Biomater 2021; 126:394-407. [PMID: 33716175 DOI: 10.1016/j.actbio.2021.03.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 02/05/2021] [Accepted: 03/05/2021] [Indexed: 12/25/2022]
Abstract
Despite tremendous progress in cell-based therapies for heart repair, many challenges still exist. To enhance the therapeutic potential of cell therapy one approach is the combination of cells with biomaterial delivery vehicles. Here, we developed a biomimetic and biodegradable micro-platform based on polymeric microparticles (MPs) capable of maximizing the therapeutic potential of cardiac progenitor cells (CPCs) and explored its efficacy in a rat model of chronic myocardial infarction. The transplantation of CPCs adhered to MPs within the infarcted myocardial microenvironment improved the long-term engraftment of transplanted cells for up to one month. Furthermore, the enhancement of cardiac cellular retention correlated with an increase in functional recovery. In consonance, better tissue remodeling and vasculogenesis were observed in the animals treated with cells attached to MPs, which presented smaller infarct size, thicker right ventricular free wall, fewer deposition of periostin and greater density of vessels than animals treated with CPCs alone. Finally, we were able to show that part of this beneficial effect was mediated by CPC-derived extracellular vesicles (EVs). Taken together, these findings indicate that the biomimetic microcarriers support stem cell survival and increase cardiac function in chronic myocardial infarction through modulation of cardiac remodeling, vasculogenesis and CPCs-EVs mediated therapeutic effects. The biomimetic microcarriers provide a solution for biomaterial-assisted CPC delivery to the heart. STATEMENT OF SIGNIFICANCE: In this study, we evaluate the possibility of using a biomimetic and biodegradable micro-platform to improve cardiovascular progenitor therapy. The strategy reported herein serves as an injectable scaffold for adherent cells due to their excellent injectability through cardiac catheters, capacity for biomimetic three-dimensional stem cell support and controllable biodegradability. In a rat model of chronic myocardial infarction, the biomimetic microcarriers improved cardiac function, reduced chronic cardiac remodeling and increased vasculogenesis through the paracrine signaling of CPCs. We have also shown that extracellular vesicles derived from CPCs cultured on biomimetic substrates display antifibrotic effects, playing an important role in the therapeutic effects of our tissue-engineered approach. Therefore, biomimetic microcarriers represent a promising and effective strategy for biomaterial-assisted CPC delivery to the heart.
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Affiliation(s)
- E Garbayo
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
| | - A Ruiz-Villalba
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Program of Regenerative Medicine, CIMA, University of Navarra, Pamplona, Spain; Department of Animal Biology, Institute of Biomedicine of Málaga (IBIMA) Faculty of Science, University of Málaga, Málaga, Spain; Andalusian Centre for Nanomedicine and Biotechnology (BIONAND), Málaga, Spain
| | - S C Hernandez
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Program of Regenerative Medicine, CIMA, University of Navarra, Pamplona, Spain
| | - L Saludas
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain
| | - G Abizanda
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Program of Regenerative Medicine, CIMA, University of Navarra, Pamplona, Spain
| | - B Pelacho
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Program of Regenerative Medicine, CIMA, University of Navarra, Pamplona, Spain
| | - C Roncal
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, Cima Universidad de Navarra, Pamplona, Spain; CIBERCV, Carlos III Institute of Health, Madrid, Spain
| | | | | | - F Prósper
- Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Program of Regenerative Medicine, CIMA, University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red (CIBERONC), Madrid, Spain.
| | - M J Blanco-Prieto
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
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Bolli R, Solankhi M, Tang XL, Kahlon A. Cell Therapy in Patients with Heart Failure: A Comprehensive Review and Emerging Concepts. Cardiovasc Res 2021; 118:951-976. [PMID: 33871588 PMCID: PMC8930075 DOI: 10.1093/cvr/cvab135] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 04/15/2021] [Indexed: 12/16/2022] Open
Abstract
This review summarizes the results of clinical trials of cell therapy in patients with heart failure (HF). In contrast to acute myocardial infarction (where results have been consistently negative for more than a decade), in the setting of HF the results of Phase I–II trials are encouraging, both in ischaemic and non-ischaemic cardiomyopathy. Several well-designed Phase II studies have met their primary endpoint and demonstrated an efficacy signal, which is remarkable considering that only one dose of cells was used. That an efficacy signal was seen 6–12 months after a single treatment provides a rationale for larger, rigorous trials. Importantly, no safety concerns have emerged. Amongst the various cell types tested, mesenchymal stromal cells derived from bone marrow (BM), umbilical cord, or adipose tissue show the greatest promise. In contrast, embryonic stem cells are not likely to become a clinical therapy. Unfractionated BM cells and cardiosphere-derived cells have been abandoned. The cell products used for HF will most likely be allogeneic. New approaches, such as repeated cell treatment and intravenous delivery, may revolutionize the field. As is the case for most new therapies, the development of cell therapies for HF has been slow, plagued by multifarious problems, and punctuated by many setbacks; at present, the utility of cell therapy in HF remains to be determined. What the field needs is rigorous, well-designed Phase III trials. The most important things to move forward are to keep an open mind, avoid preconceived notions, and let ourselves be guided by the evidence.
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Affiliation(s)
- Roberto Bolli
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292
| | - Mitesh Solankhi
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292
| | - Xiang-Liang Tang
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292
| | - Arunpreet Kahlon
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292
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Zhu D, Cheng K. Cardiac Cell Therapy for Heart Repair: Should the Cells Be Left Out? Cells 2021; 10:641. [PMID: 33805763 PMCID: PMC7999733 DOI: 10.3390/cells10030641] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/25/2021] [Accepted: 03/10/2021] [Indexed: 12/11/2022] Open
Abstract
Cardiovascular disease (CVD) is still the leading cause of death worldwide. Coronary artery occlusion, or myocardial infarction (MI) causes massive loss of cardiomyocytes. The ischemia area is eventually replaced by a fibrotic scar. From the mechanical dysfunctions of the scar in electronic transduction, contraction and compliance, pathological cardiac dilation and heart failure develops. Once end-stage heart failure occurs, the only option is to perform heart transplantation. The sequential changes are termed cardiac remodeling, and are due to the lack of endogenous regenerative actions in the adult human heart. Regenerative medicine and biomedical engineering strategies have been pursued to repair the damaged heart and to restore normal cardiac function. Such strategies include both cellular and acellular products, in combination with biomaterials. In addition, substantial progress has been made to elucidate the molecular and cellular mechanisms underlying heart repair and regeneration. In this review, we summarize and discuss current therapeutic approaches for cardiac repair and provide a perspective on novel strategies that holding potential opportunities for future research and clinical translation.
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Affiliation(s)
- Dashuai Zhu
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA;
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill & North Carolina State University, Raleigh, NC 27607, USA
| | - Ke Cheng
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA;
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill & North Carolina State University, Raleigh, NC 27607, USA
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Povsic TJ, Gersh BJ. Stem Cells in Cardiovascular Diseases: 30,000-Foot View. Cells 2021; 10:cells10030600. [PMID: 33803227 PMCID: PMC8001267 DOI: 10.3390/cells10030600] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/01/2021] [Accepted: 03/03/2021] [Indexed: 12/15/2022] Open
Abstract
Stem cell and regenerative approaches that might rejuvenate the heart have immense intuitive appeal for the public and scientific communities. Hopes were fueled by initial findings from preclinical models that suggested that easily obtained bone marrow cells might have significant reparative capabilities; however, after initial encouraging pre-clinical and early clinical findings, the realities of clinical development have placed a damper on the field. Clinical trials were often designed to detect exceptionally large treatment effects with modest patient numbers with subsequent disappointing results. First generation approaches were likely overly simplistic and relied on a relatively primitive understanding of regenerative mechanisms and capabilities. Nonetheless, the field continues to move forward and novel cell derivatives, platforms, and cell/device combinations, coupled with a better understanding of the mechanisms that lead to regenerative capabilities in more primitive models and modifications in clinical trial design suggest a brighter future.
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Affiliation(s)
- Thomas J. Povsic
- Department of Medicine, and Duke Clinical Research Institute, Duke University, Durham, NC 27705, USA
- Correspondence:
| | - Bernard J. Gersh
- Department of Cardiovascular Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA;
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Huang TH, Lee MS, Sung PH, Chen YL, Chiang JY, Yang CC, Sheu JJ, Yip HK. Quality and quantity culture effectively restores functional and proliferative capacities of endothelial progenitor cell in end-stage renal disease patients. Stem Cell Res 2021; 53:102264. [PMID: 33711688 DOI: 10.1016/j.scr.2021.102264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 02/14/2021] [Accepted: 02/16/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Endothelial cell dysfunction plays the crucial role in initiation and propagation of obstructive arteriosclerosis which ultimately causes arterial obstructive syndrome. Additionally, severe endothelial progenitor cells (EPC) dysfunction is always found in those of end-stage renal disease (ESRD) patients. This study tested the hypothesis that a novel method, named "quality and quantity (QQ) culture", could successfully improve the EPC proliferation and function in ESRD patients. MATERIALS AND METHODS Peripheral blood mononuclear cells (PBMNCs) were isolated from age-matched control subjects (i.e., normal renal function) (group 1) and ESRD patients (group 2), followed by culture in either conventional EPC culture for one month or in QQ culture for 7 days, respectively. The result showed that as compared to the conventional EPC culture method, the EPC population and M2-like population/ratio (M2/M1) were significantly enriched in QQ culture both in groups 1 and 2 (all p < 0.001), but these parameters did not differ between the groups. As compared with conventional EPC culture, the angiogenesis capacity and colony formation were significantly increased in QQ culture (all p < 0.001), but they showed no difference between groups 1 and 2. In RAW264.7 macrophages treated by liposaccharide, the gene expressions and ELISA findings of pro-inflammatory cytokines (IL-1β/IL-6/TGF-β) and inflammatory mediator (iNOS) were significantly reduced in QQ culture than in conventional EPC culture in groups 1 and 2 (all p < 0.001), but they showed no difference between the groups. CONCLUSIONS This study demonstrated that QQ culture enhanced number, proliferation, and angiogenesis of EPCs and anti-inflammatory capacity in ESRD patients.
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Affiliation(s)
- Tien-Hung Huang
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Mel S Lee
- Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Pei-Hsun Sung
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Yi-Ling Chen
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - John Y Chiang
- Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chih-Chao Yang
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Jiunn-Jye Sheu
- Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Hon-Kan Yip
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan; Department of Nursing, Asia University, Taichung 41354, Taiwan; Division of Cardiology, Department of Internal Medicine, Xiamen Chang Gung Hospital, Xiamen 361028, Fujian, China.
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Echocardiography-guided percutaneous left ventricular intracavitary injection as a cell delivery approach in infarcted mice. Mol Cell Biochem 2021; 476:2135-2148. [PMID: 33547546 DOI: 10.1007/s11010-021-04077-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 01/22/2021] [Indexed: 12/31/2022]
Abstract
In the field of cell therapy for heart disease, a new paradigm of repeated dosing of cells has recently emerged. However, the lack of a repeatable cell delivery method in preclinical studies in rodents is a major obstacle to investigating this paradigm. We have established and standardized a method of echocardiography-guided percutaneous left ventricular intracavitary injection (echo-guided LV injection) as a cell delivery approach in infarcted mice. Here, we describe the method in detail and address several important issues regarding it. First, by integrating anatomical and echocardiographic considerations, we have established strategies to determine a safe anatomical window for injection in infarcted mice. Second, we summarize our experience with this method (734 injections). The overall survival rate was 91.4%. Third, we examined the efficacy of this cell delivery approach. Compared with vehicle treatment, cardiac mesenchymal cells (CMCs) delivered via this method improved cardiac function assessed both echocardiographically and hemodynamically. Furthermore, repeated injections of CMCs via this method yielded greater cardiac function improvement than single-dose administration. Echo-guided LV injection is a feasible, reproducible, relatively less invasive and effective delivery method for cell therapy in murine models of heart disease. It is an important approach that could move the field of cell therapy forward, especially with regard to repeated cell administrations.
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Bolli R, Tang XL, Guo Y, Li Q. After the storm: an objective appraisal of the efficacy of c-kit+ cardiac progenitor cells in preclinical models of heart disease. Can J Physiol Pharmacol 2021; 99:129-139. [PMID: 32937086 PMCID: PMC8299902 DOI: 10.1139/cjpp-2020-0406] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The falsification of data related to c-kit+ cardiac progenitor cells (CPCs) by a Harvard laboratory has been a veritable tragedy. Does this fraud mean that CPCs are not beneficial in models of ischemic cardiomyopathy? At least 50 studies from 26 laboratories independent of the Harvard group have reported beneficial effects of CPCs in mice, rats, pigs, and cats. The mechanism of action remains unclear. Our group has shown that CPCs do not engraft in the diseased heart, do not differentiate into new cardiac myocytes, do not regenerate dead myocardium, and thus work via paracrine mechanisms. A casualty of the misconduct at Harvard has been the SCIPIO trial, a collaboration between the Harvard group and the group in Louisville. The retraction of the SCIPIO paper was caused exclusively by issues with data generated at Harvard, not those generated in Louisville. In the retraction notice, the Lancet editors stated: "Although we do not have any reservations about the clinical work in Louisville that used the preparations from Anversa's laboratory in good faith, the lack of reliability regarding the laboratory work at Harvard means that we are now retracting this paper". We must be careful not to dismiss all work on CPCs because of one laboratory's misconduct. An unbiased review of the literature supports the therapeutic potential of CPCs for heart failure at the preclinical level.
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Affiliation(s)
- Roberto Bolli
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA
| | - Xian-Liang Tang
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA
| | - Yiru Guo
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA
| | - Qianghong Li
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292, USA
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Carresi C, Scicchitano M, Scarano F, Macrì R, Bosco F, Nucera S, Ruga S, Zito MC, Mollace R, Guarnieri L, Coppoletta AR, Gliozzi M, Musolino V, Maiuolo J, Palma E, Mollace V. The Potential Properties of Natural Compounds in Cardiac Stem Cell Activation: Their Role in Myocardial Regeneration. Nutrients 2021; 13:275. [PMID: 33477916 PMCID: PMC7833367 DOI: 10.3390/nu13010275] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/07/2021] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases (CVDs), which include congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, and many other cardiac disorders, cause about 30% of deaths globally; representing one of the main health problems worldwide. Among CVDs, ischemic heart diseases (IHDs) are one of the major causes of morbidity and mortality in the world. The onset of IHDs is essentially due to an unbalance between the metabolic demands of the myocardium and its supply of oxygen and nutrients, coupled with a low regenerative capacity of the heart, which leads to great cardiomyocyte (CM) loss; promoting heart failure (HF) and myocardial infarction (MI). To date, the first strategy recommended to avoid IHDs is prevention in order to reduce the underlying risk factors. In the management of IHDs, traditional therapeutic options are widely used to improve symptoms, attenuate adverse cardiac remodeling, and reduce early mortality rate. However, there are no available treatments that aim to improve cardiac performance by replacing the irreversible damaged cardiomyocytes (CMs). Currently, heart transplantation is the only treatment being carried out for irreversibly damaged CMs. Hence, the discovery of new therapeutic options seems to be necessary. Interestingly, recent experimental evidence suggests that regenerative stem cell medicine could be a useful therapeutic approach to counteract cardiac damage and promote tissue regeneration. To this end, researchers are tasked with answering one main question: how can myocardial regeneration be stimulated? In this regard, natural compounds from plant extracts seem to play a particularly promising role. The present review will summarize the recent advances in our knowledge of stem cell therapy in the management of CVDs; focusing on the main properties and potential mechanisms of natural compounds in stimulating and activating stem cells for myocardial regeneration.
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Affiliation(s)
- Cristina Carresi
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Miriam Scicchitano
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Federica Scarano
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Roberta Macrì
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Francesca Bosco
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Saverio Nucera
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Stefano Ruga
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Maria Caterina Zito
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Rocco Mollace
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Lorenza Guarnieri
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Anna Rita Coppoletta
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Micaela Gliozzi
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Vincenzo Musolino
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Jessica Maiuolo
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Ernesto Palma
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
- Nutramed S.c.a.r.l., Complesso Ninì Barbieri, Roccelletta di Borgia, 88100 Catanzaro, Italy
| | - Vincenzo Mollace
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
- Nutramed S.c.a.r.l., Complesso Ninì Barbieri, Roccelletta di Borgia, 88100 Catanzaro, Italy
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43
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Evolution of Stem Cells in Cardio-Regenerative Therapy. Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Wysoczynski M, Pathan A, Moore JB, Farid T, Kim J, Nasr M, Kang Y, Li H, Bolli R. Pro-Angiogenic Actions of CMC-Derived Extracellular Vesicles Rely on Selective Packaging of Angiopoietin 1 and 2, but Not FGF-2 and VEGF. Stem Cell Rev Rep 2020; 15:530-542. [PMID: 31102187 DOI: 10.1007/s12015-019-09891-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
While the fundamental mechanism by which cardiac cell therapy mitigates ventricular dysfunction in the post ischemic heart remains poorly defined, donor cell paracrine signaling is presumed to be a chief contributor to the afforded benefits. Of the many bioactive molecules secreted by transplanted cells, extracellular vesicles (EVs) and their proteinaceous, nucleic acid, and lipid rich contents, comprise a heterogeneous assortment of prospective cardiotrophic factors-whose involvement in the activation of endogenous cardiac repair mechanism(s), including reducing fibrosis and promoting angiogenesis, have yet to be fully explained. In the current study we aimed to interrogate potential mechanisms by which cardiac mesenchymal stromal cell (CMC)-derived EVs contribute to the CMC pro-angiogenic paracrine signaling capacity in vitro. Vesicular transmission and biological activity of human CMC-derived EVs was evaluated in in vitro assays for human umbilical vein endothelial cell (HUVEC) function, including EV uptake, cell survival, migration, tube formation, and intracellular pathway activation. HUVECs incubated with EVs exhibited augmented cell migration, tube formation, and survival under peroxide exposure; findings which paralleled enhanced activation of the archetypal pro-survival/pro-angiogenic pathways, STAT3 and PI3K-AKT. Cytokine array analyses revealed preferential enrichment of a subset of prototypical angiogenic factors, Ang-1 and Ang-2, in CMC EVs. Interestingly, pharmacologic inhibition of Tie2 in HUVECs, the cognate receptors of angiopoietins, efficiently attenuated CMC-EV-induced HUVEC migration. Further, in additional assays a Tie2 kinase inhibitor exhibited specificity to inhibit Ang-1-, but not Ang-2-, induced HUVEC migration. Overall, these findings suggest that the pro-angiogenic activities of CMC EVs are principally mediated by Ang-1-Tie2 signaling.
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Affiliation(s)
- Marcin Wysoczynski
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA.
- University of Louisville, 580 South Preston St. - Rm 119F, Louisville, KY, 40202, USA.
| | - Asif Pathan
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Joseph B Moore
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Talha Farid
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Jae Kim
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Marjan Nasr
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Yi Kang
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Hong Li
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Roberto Bolli
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA.
- University of Louisville, 550 S Jackson St.- ACB, Third Floor, Louisville, KY, 40292, USA.
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45
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Kraus L, Ma L, Yang Y, Nguyen F, Hoy RC, Okuno T, Khan M, Mohsin S. Cortical Bone Derived Stem Cells Modulate Cardiac Fibroblast Response via miR-18a in the Heart After Injury. Front Cell Dev Biol 2020; 8:494. [PMID: 32656212 PMCID: PMC7324629 DOI: 10.3389/fcell.2020.00494] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 05/25/2020] [Indexed: 12/29/2022] Open
Abstract
The adult heart following injury such as a myocardial infarction forms a fibrotic scar associated with transformation of resident cardiac fibroblasts into myofibroblast, accelerating cardiac remodeling and dysfunction. Cell therapies provide a novel direction for the enhancement of cardiac structure and function but remain poorly described in terms of the effect on resident cardiac fibroblasts. We have shown cortical bone derived stem cells (CBSCs) exhibit an ability to repair the heart after myocardial injury together with reduced scar formation. Nevertheless, whether CBSCs possess ability to modulate resident fibroblast response after myocardial injury remains untested.
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Affiliation(s)
- Lindsay Kraus
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Lena Ma
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Yijun Yang
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Faustina Nguyen
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Robert C Hoy
- Center for Metabolic Disease, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Tomoko Okuno
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Mohsin Khan
- Center for Metabolic Disease, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Sadia Mohsin
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
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46
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Audam TN, Nong Y, Tomlin A, Jurkovic A, Li H, Zhu X, Long BW, Zheng YW, Weirick T, Brittian KR, Riggs DW, Gumpert A, Uchida S, Guo Y, Wysoczynski M, Jones SP. Cardiac mesenchymal cells from failing and nonfailing hearts limit ventricular dilation when administered late after infarction. Am J Physiol Heart Circ Physiol 2020; 319:H109-H122. [PMID: 32442025 DOI: 10.1152/ajpheart.00114.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Although cell therapy-mediated cardiac repair offers promise for treatment/management of heart failure, lack of fundamental understanding of how cell therapy works limits its translational potential. In particular, whether reparative cells from failing hearts differ from cells derived from nonfailing hearts remains unexplored. Here, we assessed differences between cardiac mesenchymal cells (CMC) derived from failing (HF) versus nonfailing (Sham) hearts and whether the source of donor cells (i.e., from HF vs. Sham) limits reparative capacity, particularly when administered late after infarction. To determine the impact of the donor source of CMCs, we characterized the transcriptional profile of CMCs isolated from sham (Sham-CMC) and failing (HF-CMC) hearts. RNA-seq analysis revealed unique transcriptional signatures in Sham-CMC and HF-CMC, suggesting that the donor source impacts CMC. To determine whether the donor source affects reparative potential, C57BL6/J female mice were subjected to 60 min of regional myocardial ischemia and then reperfused for 35 days. In a randomized, controlled, and blinded fashion, vehicle, HF-CMC, or Sham-CMC were injected into the lumen of the left ventricle at 35 days post-MI. An additional 5 weeks later, cardiac function was assessed by echocardiography, which indicated that delayed administration of Sham-CMC and HF-CMC attenuated ventricular dilation. We also determined whether Sham-CMC and HF-CMC treatments affected ventricular histopathology. Our data indicate that the donor source (nonfailing vs. failing hearts) affects certain aspects of CMC, and these insights may have implications for future studies. Our data indicate that delayed administration of CMC limits ventricular dilation and that the source of CMC may influence their reparative actions.NEW & NOTEWORTHY Most preclinical studies have used only cells from healthy, nonfailing hearts. Whether donor condition (i.e., heart failure) impacts cells used for cell therapy is not known. We directly tested whether donor condition impacted the reparative effects of cardiac mesenchymal cells in a chronic model of myocardial infarction. Although cells from failing hearts differed in multiple aspects, they retained the potential to limit ventricular remodeling.
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Affiliation(s)
- Timothy N Audam
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Yibing Nong
- Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Alex Tomlin
- Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Andrea Jurkovic
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Hong Li
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Xiaoping Zhu
- Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Bethany W Long
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Yi Wei Zheng
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Tyler Weirick
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky.,Cardiovascular Innovation Institute, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Kenneth R Brittian
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Daniel W Riggs
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Anna Gumpert
- Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Shizuka Uchida
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky.,Cardiovascular Innovation Institute, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Yiru Guo
- Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Marcin Wysoczynski
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Steven P Jones
- Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, Kentucky
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Morrissette-McAlmon J, Ginn B, Somers S, Fukunishi T, Thanitcul C, Rindone A, Hibino N, Tung L, Mao HQ, Grayson W. Biomimetic Model of Contractile Cardiac Tissue with Endothelial Networks Stabilized by Adipose-Derived Stromal/Stem Cells. Sci Rep 2020; 10:8387. [PMID: 32433563 PMCID: PMC7239907 DOI: 10.1038/s41598-020-65064-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 04/23/2020] [Indexed: 11/15/2022] Open
Abstract
Cardiac tissue engineering strategies have the potential to regenerate functional myocardium following myocardial infarction. In this study, we utilized novel electrospun fibrin microfiber sheets of different stiffnesses (50.0 ± 11.2 kPa and 90.0 ± 16.4 kPa) to engineer biomimetic models of vascularized cardiac tissues. We characterized tissue assembly, electrophysiology, and contractility of neonatal rat ventricular cardiomyocytes (NRVCMs) cultured on these sheets. NRVCMs cultured on the softer substrates displayed higher conduction velocities (CVs) and improved electrophysiological properties. Human umbilical vein endothelial cells (HUVECs) formed dense networks on the sheets when co-cultured with human adipose-derived stem/stromal cells (hASCs). To achieve vascularized cardiac tissues, we tested various tri-culture protocols of NRVCM:hASC:HUVEC and found that a ratio of 1,500,000:37,500:150,000 cells/cm2 enabled the formation of robust endothelial networks while retaining statistically identical electrophysiological characteristics to NRVCM-only cultures. Tri-cultures at this ratio on 90 kPa substrates exhibited average CVs of 14 ± 0.6 cm/s, Action Potential Duration (APD)80 and APD30 of 152 ± 11 ms and 71 ± 6 ms, respectively, and maximum capture rate (MCR) of 3.9 ± 0.7 Hz. These data indicate the significant potential of generating densely packed endothelial networks together with electrically integrated cardiac cells in vitro as a physiologic 3D cardiac model.
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Affiliation(s)
- Justin Morrissette-McAlmon
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Brian Ginn
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Material Sciences & Engineering, Johns Hopkins University, School of Engineering, Baltimore, MD, USA
| | - Sarah Somers
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Takuma Fukunishi
- Department of Surgery & Cardiac Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Chanon Thanitcul
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Alexandra Rindone
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Narutoshi Hibino
- Department of Surgery & Cardiac Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Leslie Tung
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Hai-Quan Mao
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Material Sciences & Engineering, Johns Hopkins University, School of Engineering, Baltimore, MD, USA
- Institute for NanoBioTechnology (INBT), Johns Hopkins University School of Engineering, Baltimore, MD, USA
| | - Warren Grayson
- Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Material Sciences & Engineering, Johns Hopkins University, School of Engineering, Baltimore, MD, USA.
- Institute for NanoBioTechnology (INBT), Johns Hopkins University School of Engineering, Baltimore, MD, USA.
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Dergilev KV, Vasilets ID, Tsokolaeva ZI, Zubkova ES, Parfenova EV. [Perspectives of cell therapy for myocardial infarction and heart failure based on cardiosphere cells]. TERAPEVT ARKH 2020; 92:111-120. [PMID: 32598708 DOI: 10.26442/00403660.2020.04.000634] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Indexed: 12/13/2022]
Abstract
Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. In recent years, researchers are attracted to the use of cell therapy based on stem cell and progenitor cells, which has been a promising strategy for cardiac repair after injury. However, conducted research using intracoronary or intramyocardial transplantation of various types of stem/progenitor cells as a cell suspension showed modest efficiency. This is due to the low degree of integration and cell survival after transplantation. To overcome these limitations, the concept of the use of multicellular spheroids modeling the natural microenvironment of cells has been proposed, which allows maintaining their viability and therapeutic properties. It is of great interest to use so-called cardial spheroids (cardiospheres) spontaneously forming three-dimensional structures under low-adhesive conditions, consisting of a heterogeneous population of myocardial progenitor cells and extracellular matrix proteins. This review presents data on methods for creating cardiospheres, directed regulation of their properties and reparative potential, as well as the results of preclinical and clinical studies on their use for the treatment of heart diseases.
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Affiliation(s)
| | | | - Z I Tsokolaeva
- National Medical Research Center for Cardiology.,Negovsky Scientific Research Institute of General Reanimatology of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology
| | - E S Zubkova
- National Medical Research Center for Cardiology
| | - E V Parfenova
- National Medical Research Center for Cardiology.,Lomonosov Moscow State University
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49
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Ozaki Tan SJ, Floriano JF, Nicastro L, Emanueli C, Catapano F. Novel Applications of Mesenchymal Stem Cell-derived Exosomes for Myocardial Infarction Therapeutics. Biomolecules 2020; 10:E707. [PMID: 32370160 PMCID: PMC7277090 DOI: 10.3390/biom10050707] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 04/22/2020] [Accepted: 04/27/2020] [Indexed: 02/07/2023] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity globally, representing approximately a third of all deaths every year. The greater part of these cases is represented by myocardial infarction (MI), or heart attack as it is better known, which occurs when declining blood flow to the heart causes injury to cardiac tissue. Mesenchymal stem cells (MSCs) are multipotent stem cells that represent a promising vector for cell therapies that aim to treat MI due to their potent regenerative effects. However, it remains unclear the extent to which MSC-based therapies are able to induce regeneration in the heart and even less clear the degree to which clinical outcomes could be improved. Exosomes, which are small extracellular vesicles (EVs) known to have implications in intracellular communication, derived from MSCs (MSC-Exos), have recently emerged as a novel cell-free vector that is capable of conferring cardio-protection and regeneration in target cardiac cells. In this review, we assess the current state of research of MSC-Exos in the context of MI. In particular, we place emphasis on the mechanisms of action by which MSC-Exos accomplish their therapeutic effects, along with commentary on the current difficulties faced with exosome research and the ongoing clinical applications of stem-cell derived exosomes in different medical contexts.
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Affiliation(s)
- Sho Joseph Ozaki Tan
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (S.J.O.T.); (J.F.F.); (L.N.)
| | - Juliana Ferreria Floriano
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (S.J.O.T.); (J.F.F.); (L.N.)
- Botucatu Medical School, Sao Paulo State University, Botucatu 18618687, Brazil
| | - Laura Nicastro
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (S.J.O.T.); (J.F.F.); (L.N.)
| | - Costanza Emanueli
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (S.J.O.T.); (J.F.F.); (L.N.)
| | - Francesco Catapano
- National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; (S.J.O.T.); (J.F.F.); (L.N.)
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Wagner MJ, Khan M, Mohsin S. Healing the Broken Heart; The Immunomodulatory Effects of Stem Cell Therapy. Front Immunol 2020; 11:639. [PMID: 32328072 PMCID: PMC7160320 DOI: 10.3389/fimmu.2020.00639] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 03/20/2020] [Indexed: 12/14/2022] Open
Abstract
Cardiovascular Disease (CVD) is a leading cause of mortality within the United States. Current treatments being administered to patients who suffered a myocardial infarction (MI) have increased patient survival, but do not facilitate the replacement of damaged myocardium. Recent studies demonstrate that stem cell-based therapies promote myocardial repair; however, the poor engraftment of the transferred stem cell populations within the infarcted myocardium is a major limitation, regardless of the cell type. One explanation for poor cell retention is attributed to the harsh inflammatory response mounted following MI. The inflammatory response coupled to cardiac repair processes is divided into two distinct phases. The first phase is initiated during ischemic injury when necrosed myocardium releases Danger Associated Molecular Patterns (DAMPs) and chemokines/cytokines to induce the activation and recruitment of neutrophils and pro-inflammatory M1 macrophages (MΦs); in turn, facilitating necrotic tissue clearance. During the second phase, a shift from the M1 inflammatory functional phenotype to the M2 anti-inflammatory and pro-reparative functional phenotype, permits the resolution of inflammation and the establishment of tissue repair. T-regulatory cells (Tregs) are also influential in mediating the establishment of the pro-reparative phase by directly regulating M1 to M2 MΦ differentiation. Current studies suggest CD4+ T-lymphocyte populations become activated when presented with autoantigens released from the injured myocardium. The identity of the cardiac autoantigens or paracrine signaling molecules released from the ischemic tissue that directly mediate the phenotypic plasticity of T-lymphocyte populations in the post-MI heart are just beginning to be elucidated. Stem cells are enriched centers that contain a diverse paracrine secretome that can directly regulate responses within neighboring cell populations. Previous studies identify that stem cell mediated paracrine signaling can influence the phenotype and function of immune cell populations in vitro, but how stem cells directly mediate the inflammatory microenvironment of the ischemic heart is poorly characterized and is a topic of extensive investigation. In this review, we summarize the complex literature that details the inflammatory microenvironment of the ischemic heart and provide novel insights regarding how paracrine mediated signaling produced by stem cell-based therapies can regulate immune cell subsets to facilitate pro-reparative myocardial wound healing.
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Affiliation(s)
- Marcus J Wagner
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Mohsin Khan
- Center for Metabolic Disease, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.,Department of Physiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
| | - Sadia Mohsin
- Independence Blue Cross Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States.,Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States
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